bluuebunny/crossref_metadata_2025 huggingface dataset:
Cloning and characterization of tetM gene from a Ureaplasma urealyticum strain
Authors: Brown J T , Roberts M C
Published: June 2012

We have cloned a 4.9-kilobase (kb) HincII fragment which contains a tetracycline resistance determinant (tetM) from the chromosome of Ureaplasma urealyticum. The 4.9-kb HincII fragment contains DNA in addition to the structural gene, is closely related to the previously characterized 5.0-kb fragment from pJI3, and contains no normal ureaplasmal DNA sequences.
Correction for bacterial loss in in vitro dilution models
Authors: White C A , Toothaker R D , Smith A L , Slattery J T
Published: June 2012

A new method to correct for bacteria lost to dilution in in vitro kinetic models is presented which includes the influence of the stationary bacterial growth phase. The method imposes an upper limit on bacterial density, in contrast to previous methods.
Formulation, toxicity, and antifungal activity in vitro of liposome-encapsulated nystatin as therapeutic agent for systemic candidiasis
Authors: Mehta R T , Hopfer R L , Gunner L A , Juliano R L , Lopez-Berestein G
Published: June 2012

Multilamellar vesicles containing nystatin (NYS) were compared with vesicles containing the free drug for toxicity to erythrocytes and for antifungal activity in vitro. Liposomal nystatin was as active as free NYS was against a wide variety of yeasts and fungi. The antifungal activity against Candida albicans was maintained with different liposome compositions and without sterols. Liposome encapsulation also protected the erythrocytes from the toxicity of free NYS.
Toxicity and therapeutic effects in mice of liposome-encapsulated nystatin for systemic fungal infections
Authors: Mehta R T , Hopfer R L , McQueen T , Juliano R L , Lopez-Berestein G
Published: June 2012

The therapeutic activity of nystatin (NYS) incorporated in multilamellar liposomes (L-NYS) was studied in vivo. Hale-Stoner mice injected intravenously with various doses of L-NYS and free NYS showed a significant reduction in toxicity of NYS after the NYS was incorporated into liposomes (maximal tolerated doses, 16 and 4 mg/kg of body weight, respectively). The maximal tolerated dose of free NYS had no effect in the treatment of mice infected with Candida albicans, whereas L-NYS at an equivalent dose improved the survival of mice. A marked increase in survival was observed when L-NYS was administered in higher and multiple doses (total doses up to 80 mg/kg). Liposome encapsulation thus provided a means for intravenous administration of NYS, reducing its toxicity and making it an active systemic antifungal agent.
High-performance liquid chromatography measurement of antimicrobial concentrations in polymorphonuclear leukocytes
Authors: Koga H
Published: June 2012

High-performance liquid chromatography was used to determine the penetration of 19 antimicrobial agents into human polymorphonuclear leukocytes. The ratios of the intracellular concentration to the extracellular concentration of ampicillin, piperacillin, cefazolin, ceftizoxime, cefpimizole, and ceftazidime were all less than 0.6. Lincomycin showed a high intracellular-to-extracellular ratio (3.0), while clindamycin achieved a ratio of 15.5, which was the highest ratio of all of the 19 tested antibiotics. Ratios for rifampin, isoniazid, chloramphenicol, and trimethoprim were 8.2, 1.1, 9.6, and 6.1, respectively. Six quinolone-class antimicrobial agents had ratios from 2.2 to 8.2. Flucytosine showed a penetration ratio of 4.6. Clindamycin uptake was temperature dependent and occurred best with live polymorphonuclear leukocytes; sodium fluoride, adenosine, and puromycin were inhibitory. The results obtained in this study correlate well with the results of other studies involving radioisotopic methods. This indicates that high-performance liquid chromatography is a useful method for determining the intracellular penetration of antimicrobial agents.
A40926, a new glycopeptide antibiotic with anti-Neisseria activity
Authors: Goldstein B P , Selva E , Gastaldo L , Berti M , Pallanza R , Ripamonti F , Ferrari P , Denaro M , Arioli V , Cassani G
Published: June 2012

In the course of a search for glycopeptide antibiotics having novel biological properties, we isolated A40926. Produced by an actinomycete of the genus Actinomadura, A40926 is a complex of four main factors which contain a fatty acid as part of a glycolipid attached to the peptide backbone. Its activity was, in most respects, similar to that of other glycopeptides, such as vancomycin and teicoplanin. However, in addition to inhibiting gram-positive bacteria, A40926 was very active against Neisseria gonorrhoeae. A40926 was rapidly bactericidal for N. gonorrhoeae clinical isolates at concentrations equal to or slightly higher than the MIC. In mice, levels in serum were higher and more prolonged than those of an equivalent subcutaneous dose of teicoplanin. These properties suggest that A40926 may have potential in the therapy of gonorrhea.
In vitro susceptibilities of suspected periodontopathic anaerobes as determined by membrane transfer assay
Authors: Caufield P W , Allen D N , Childers N K
Published: June 2012

Attempts to devise an antimicrobial approach to combating dentomicrobial infections such as periodontal diseases continue to be hampered by the lack of a relevant in vitro method for determining the susceptibility of suspected periodontopathogens to topically applied antimicrobial agents. Proposed here is a novel in vitro method called the membrane transfer technique, which acknowledges those aspects unique to localized pathogenic infections, particularly those associated with anaerobic bacteria. Bacterial lawns representing six suspected periodontopathic bacteria were prepared on membranes and then placed in contact with different concentrations of antimicrobial agents for 5 min. After incubation for 12 to 24 h, MBCs were determined with the aid of a tetrazolium chloride indicator. Four antimicrobial agents (chlorhexidine, iodine, stannous fluoride, and sodium fluoride) were used to test the applicability of the proposed in vitro method. MBCs were derived for each agent except sodium fluoride against all or most of the six bacterial strains tested. The proposed method may also be useful for examining the bactericidal action of topically applied antimicrobial agents against nonoral infections.
Effect of minimal amounts of thymidine on activity of trimethoprim-sulfamethoxazole against Staphylococcus epidermidis
Authors: Jones C , Stevens D L , Ojo O
Published: June 2012

The antibacterial activity of trimethoprim-sulfamethoxazole against 99 strains of Staphylococcus epidermidis was tested on media known to be low in thymidine content, as determined by screening with Streptococcus faecalis. Eighty-one percent of the isolates were susceptible by agar dilution. Trimethoprim-sulfamethoxazole was bactericidal against two strains of S. epidermidis when thymidine phosphorylase was added to the medium, indicating utilization of minimal amounts of thymidine that were undetected by screening. Because bacteria vary in their utilization of thymidine and body tissues vary in thymidine content, in vitro susceptibility tests may not correlate with in vivo bactericidal activity.
Pharmacokinetics and tissue penetration of Ro 23-6240, a new trifluoroquinolone
Authors: Wise R , Kirkpatrick B , Ashby J , Griggs D J
Published: June 2012

A 400-mg dose of the trifluorinated quinolone Ro 23-6240 was administered orally to each of six healthy male volunteers, after which the concentrations of this agent in serum and cantharidin-induced inflammatory fluid were measured. Absorption was rapid, with a mean peak level in serum of 6.1 micrograms/ml, which was attained 0.71 h after administration. The elimination half-life in serum was 11.95 h. The agent penetrated the inflammatory fluid rapidly; the percent penetration was 89.7%. Urinary recovery of Ro 23-6240 was 58.6% by 72 h.
Comparison of histologic and quantitative techniques in evaluation of therapy for experimental Pneumocystis carinii pneumonia
Authors: Kim C K , Foy J M , Cushion M T , Stanforth D , Linke M J , Hendrix H L , Walzer P D
Published: June 2012

Pneumocystis carinii pneumonia was induced in rats by the administration of corticosteroids, and histologic and quantitative techniques were compared in the evaluation of the severity of the disease and response to therapy. A highly significant correlation was found between the histologic score of the extent of alveolar involvement (the standard method of assessment) and the number of P. carinii cysts and nuclei in lung homogenates, lung weight, and lung weight/body weight ratio. Clear differences were noted between rats which responded well and rats which responded poorly to therapy by all techniques. Quantitation of P. carinii cysts and nuclei revealed a 10(4)-fold reduction in organism burden with successful treatment. Thus, these techniques should be helpful in the development of testing of new antimicrobial agents in the rat model of pneumocystosis.
Clinical evaluation of efficacy, pharmacokinetics, and safety of teicoplanin for serious gram-positive infections
Authors: Bibler M R , Frame P T , Hagler D N , Bode R B , Staneck J L , Thamlikitkul V , Harris J E , Haregewoin A , Bullock W E
Published: June 2012

Nineteen patients hospitalized for serious gram-positive infections were treated with teicoplanin, a new glycopeptide antibiotic. A variety of infections were treated, including endocarditis, septic thrombophlebitis, osteomyelitis, pyogenic arthritis, and soft tissue infection. Of 13 infections that could be evaluated in 12 patients, there were 8 clinical cures, 2 improvements, 1 recurrence, and 2 failures. Of the eight patients with Staphylococcus aureus bacteremia, seven were clinically cured or improved with teicoplanin therapy. Of the nine patients in whom the bacteriological response to treatment could be fully evaluated, six were cured; there was recurrence of infection in one, and treatment failed in two patients. In vitro testing showed the 13 bacterial isolates (9 S. aureus, 3 S. epidermidis, and 1 group B streptococcus) to be uniformly susceptible to teicoplanin, with MICs ranging from 0.12 to 0.5 microgram/ml. Every isolate was more susceptible in vitro to teicoplanin than to vancomycin. Three of the staphylococcal isolates were resistant to methicillin. Pharmacokinetic studies demonstrated that after an initial drug-accumulation period, a single daily dose adequately maintained the teicoplanin concentrations in serum within therapeutic ranges. Teicoplanin also penetrated well into synovial fluid. The drug was well tolerated by either intravenous or intramuscular administration. The most significant adverse reaction was an urticarial rash which required discontinuation of therapy in one patient; a second patient experienced a modest decrease in high-frequency auditory threshold. Asymptomatic eosinophilia and mild elevation of serum transaminases were noted as well. The results of this study suggest that teicoplanin is a safe and effective new agent for treatment of serious infections caused by gram-positive organisms.
Decreased binding of antibiotics to lipopolysaccharides from polymyxin-resistant strains of Escherichia coli and Salmonella typhimurium
Authors: Peterson A A , Fesik S W , McGroarty E J
Published: June 2012

The interactions of polycationic antibiotics with lipopolysaccharide (LPS) isolated from parental and polymyxin-resistant strains of Salmonella typhimurium and Escherichia coli were measured by using a cationic spin probe. Electron spin resonance spectra indicated that increasing concentrations of cations competitively displaced probe from LPS aggregates. Polymyxin B and other cations displaced less probe from LPS of polymyxin-resistant strains than from LPS of the parental strains, whereas the same amount or more probe was displaced from isolates of the mutants by the structurally similar antibiotic, EM 49 (octapeptin). In general, the differential affinities of these antibiotics for LPS correlated with their antibiotic activity in vivo, suggesting that resistance results from a decrease in antibiotic permeability across the outer membrane due to alterations in the LPS which affect antibiotic binding. The alterations in the structure of LPS from the polymyxin-resistant mutants of E. coli were characterized using 31P nuclear magnetic resonance spectroscopy. The results suggested that esterification of the core-lipid A phosphates is responsible for increased resistance to polymyxin B and that this alteration is different from that previously proposed for the S. typhimurium strains. In both cases, however, resistance was the result of modifications that result in a less acidic lipid A.
Susceptibility of Mobiluncus species to 23 antimicrobial agents and 15 other compounds
Authors: Spiegel C A
Published: June 2012

The susceptibility of 12 strains of Mobiluncus curtisii and 10 strains of M. mulieris to 23 antimicrobial agents and 15 other compounds was determined. All strains were susceptible to chloramphenicol, clindamycin, rifampin, tobramycin, vancomycin, virginiamycin, and all beta-lactam antibiotics tested, including imipenem. One strain of M. mulieris was resistant to erythromycin and josamycin. All were resistant to colistin, cycloserine, nalidixic acid, and neomycin. Tetracycline had variable activity. All M. curtisii strains were resistant to metronidazole and its hydroxy metabolite. Of 10 M. mulieris strains, 5 were resistant to metronidazole and 2 were resistant to its hydroxy metabolite. All 12 M. curtisii and 1 of 10 M. mulieris strains were resistant to tinidazole. M. curtisii and M. mulieris produced two mutually exclusive clusters of MICs when tested against ampicillin, cefoxitin, cephalothin, moxalactam, alizarin red, Evans blue, and sodium fluoride. Gardnerella vaginalis was more susceptible to Nile blue A than was either M. curtisii or M. mulieris. Clindamycin and imipenem may be useful agents in the therapy of metronidazole-resistant bacterial vaginosis. Metronidazole, tinidazole, and Nile blue A may be of value in the development of a selective agar for Mobiluncus species.
Role of beta-lactamase in in vivo development of ceftazidime resistance in experimental Pseudomonas aeruginosa endocarditis
Authors: Bayer A S , Peters J , Parr T R , Chan L , Hancock R E
Published: June 2012

Two ceftazidime-resistant variants of Pseudomonas aeruginosa (PA-48, PA-60), obtained from cardiac vegetations of rabbits with endocarditis receiving ceftazidime therapy, were studied for mechanisms of resistance. Both resistant variants were stably derepressed for the type Id beta-lactamase, which was ceftazidime inducible in the parental strain (PA-96) used to initially infect the rabbits. There was no evidence of ceftazidime bioinactivation by the resistant strains, and their outer membrane permeabilities were comparable to those of the parental strain. No alterations were observed in patterns of outer membrane proteins or membrane lipopolysaccharides in the resistant variants as compared with the parental strain. Penicillin-binding protein patterns of the resistant variants revealed the absence of penicillin-binding protein 4 in both, with acquisition of a new protein of higher apparent molecular weight in PA-60. Calculation of the rate of appearance of ceftazidime in the periplasm at sub-MICs suggested that slow enzymatic hydrolysis of the beta-lactam, rather than nonhydrolytic trapping, was the major explanation for the induced resistance in vivo in strains PA-48 and PA-60.
Comparison of single and combination antimicrobial agents for prevention of experimental gas gangrene caused by Clostridium perfringens
Authors: Stevens D L , Laine B M , Mitten J E
Published: June 2012

The treatment of experimental gas gangrene caused by Clostridium perfringens was investigated by using combinations of antimicrobial agents. This study demonstrated that rifampin, penicillin, metronidazole, and clindamycin were all bactericidal against standard inocula (10(5) to 10(6) CFU). These antimicrobial agents were then administered to mice beginning 30 min after intramuscular injection of 10(9) CFU of C. perfringens type A. The highest doses used produced levels of drug in blood which exceeded the MIC by at least a factor of 40. In addition, other groups of mice received monotherapy at full dose or one-fourth full dose or combination antimicrobial therapy at full or one-fourth full dose. Among the single and combination antimicrobial treatments, metronidazole alone, clindamycin alone, and clindamycin plus penicillin were the most efficacious (P less than 0.05). Although the survival of mice treated with clindamycin plus penicillin was greater than that of mice treated with clindamycin alone, the difference did not reach statistical significance (P greater than 0.05). In contrast, mice treated with a combination of metronidazole and penicillin demonstrated greater mortality than those treated with metronidazole alone (P less than 0.05). In summary, combination antimicrobial therapy of experimental C. perfringens infection did not improve survival compared to that achieved with metronidazole or clindamycin alone, and some combinations significantly reduced survival (P less than 0.05).
Impaired clearance of ceftizoxime and cefotaxime after orthotopic liver transplantation
Authors: Burckart G J , Ptachcinski R J , Jones D H , Howrie D L , Venkataramanan R , Starzl T E
Published: June 2012

The pharmacokinetics of ceftizoxime (CZX) and of cefotaxime (CTX) were studied in five children and five adults after orthotopic liver transplantation (OLT). Delayed clearance of CZX (clearance of 0.21 to 1.26 ml/min per kg [body weight]) and CTX (clearance of 0.40 to 1.49 ml/min per kg) occurred in 7 of the 10 OLT patients. We conclude that abnormal CZX and CTX clearance is common after OLT and may be associated with minimal change in serum creatinine.
In vitro activity of A-56268 (TE-031), a new macrolide, compared with that of erythromycin and clindamycin against selected gram-positive and gram-negative organisms
Authors: Benson C A , Segreti J , Beaudette F E , Hines D W , Goodman L J , Kaplan R L , Trenholme G M
Published: June 2012

The in vitro activity of A-56268 was determined and compared with that of erythromycin and clindamycin against a limited spectrum of 401 gram-positive and gram-negative organisms. A-56268 was quite active against erythromycin-susceptible Staphylococcus aureus, Neisseria gonorrhoeae, Listeria monocytogenes, Streptococcus pneumoniae, Streptococcus pyogenes, and group B streptococci and was moderately active against Campylobacter fetus subsp. fetus. A-56268 was consistently bactericidal only for S. pneumoniae. The activity of A-56268 was comparable to that of erythromycin against most organisms tested.
In vitro susceptibility of Capnocytophaga species to antimicrobial agents
Authors: Hawkey P M , Smith S D , Haynes J , Malnick H , Forlenza S W
Published: June 2012

A total of 33 clinical isolates of Capnocytophaga spp. were susceptible to 4-quinolone antimicrobial agents. The antipseudomonal penicillins tested were equally active against all isolates, as were cefuroxime, ceftriaxone, ceftizoxime, cefotaxime, latamoxef, and ceftazidime. Most isolates were resistant to trimethoprim, and some were resistant to aztreonam. Most regimens for the empirical treatment of septic episodes in immunocompromised patients are suitable for the treatment of Capnocytophaga spp. infections.
Comparative antibacterial activity of Vancocin and generic vancomycin
Authors: Conte J E
Published: June 2012

The in vitro antibacterial activity of generic vancomycin was compared with that of Vancocin (vancomycin hydrochloride; Eli Lilly & Co.) using macrotube dilution testing and subculture. There were no significant differences in MICs or MBCs of the two drugs when tested against a variety of recently isolated hospital pathogens.
In vitro activity of a new macrolide, A-56268, compared with that of roxithromycin, erythromycin, and clindamycin
Authors: Barry A L , Thornsberry C , Jones R N
Published: June 2012

A new macrolide (A-56268) was found to be approximately twice as active as erythromycin and four to eight times more active than roxithromycin. All three macrolides were similar in their potency against anaerobes. Human plasma enhanced the antistaphylococcal activity of A-56268 and erythromycin but reduced the activities of roxithromycin and clindamycin.
In vivo synergism of roxithromycin (RU 965) and interferon against Toxoplasma gondii
Authors: Hofflin J M , Remington J S
Published: June 2012

We investigated the activity of roxithromycin (RU 965) and gamma interferon alone and in combination in a murine model of toxoplasmic encephalitis. Roxithromycin at a dosage of 35 or 50 mg per mouse per day decreased mortality. Gamma interferon alone significantly prolonged time to death. When combined, the two agents were remarkably synergistic.
Concentration of norfloxacin in human gallbladder tissue and bile after single-dose oral administration
Authors: Dan M , Serour F , Gorea A , Levenberg A , Krispin M , Berger S A
Published: June 2012

Concomitant concentrations of norfloxacin in serum and in gallbladder tissue and bile were determined in 10 patients after a single oral dose of 400 mg given before cholecystectomy. Concentrations in gallbladder bile ranged from 0.6 to 15.6 micrograms/ml, with a mean bile/serum ratio of 7.0. The mean concentration in gallbladder tissue was 1.8 +/- 0.8 (standard error) micrograms/g.
Demonstration of viral thymidine kinase inhibitor and its effect on deoxynucleotide metabolism in cells infected with herpes simplex virus
Authors: Nutter L M , Grill S P , Dutschman G E , Sharma R A , Bobek M , Cheng Y C
Published: June 2012

The thymidine analog 5'-ethynylthymidine was a potent inhibitor of herpes simplex virus type 1 (strain KOS)-induced thymidine kinase with a Ki value of 0.09 microM. 5'-Ethynylthymidine was less inhibitory against herpes simplex virus type 2 (strain 333)-induced thymidine kinase with a Ki of 0.38 microM and showed no inhibition against human cytosolic thymidine kinase under the conditions tested. The compound was effective against the altered thymidine kinase induced by acyclovir- and bromovinyldeoxyuridine-resistant virus variants. At 100 microM 5'-ethynylthymidine, the cellular pool size of dTTP in herpes simplex virus type 1-infected cells was 5% that of infected cells receiving no drug treatment, while there was no significant effect on the pool sizes of dATP, dGTP, and dCTP. There was a positive correlation between dTTP pools and the intracellular thymidine kinase activity of herpes simplex virus type 1-infected cells. When tested alone, 5'-ethynylthymidine exhibited no antiviral activity, but it antagonized the antiviral efficacy of five compounds which require viral thymidine kinase for their action.
Effect of lipid composition and liposome size on toxicity and in vitro fungicidal activity of liposome-intercalated amphotericin B
Authors: Szoka F C , Milholland D , Barza M
Published: June 2012

Intercalation of amphotericin B into liposomes at a 10 mol% drug/lipid ratio decreased its cytotoxicity by 3- to 90-fold in cultured murine cells and reduced its lethality by 2- to 8-fold in a median lethal dose (LD50) test in mice when compared with the commercial deoxycholate-solubilized drug (LD50 = 2.3 mg/kg). The cytotoxicity and lethality of the liposomal preparations were a function of their lipid composition and diameter. There was no correlation between the reduction of toxicity in the tissue culture assay and the reduction of lethality in the LD50 test. The rank order of reduction of lethality was sterol-containing liposomes greater than solid liposomes greater than fluid liposomes. In general, small sterol-containing vesicles were less lethal than large vesicles of the same composition. Intercalation of amphotericin B in sterol or solid liposomes increased not only the LD50 but also the time to death. The organ distribution of amphotericin B 24 h after intravenous administration was similar whether the drug was given as the commercial deoxycholate preparation or in liposomes. Finally, there were no differences among any of the formulations in their fungicidal activity against Candida tropicalis and Saccharomyces cerevisiae in vitro. The lesser and slower lethality of the liposomal and detergent-solubilized drug suggests that the mechanism by which liposomes reduce the lethality of amphotericin B is by slowing its rate of transfer to a sensitive cellular target.
Bowel flora changes in humans receiving cefixime (CL 284,635) or cefaclor
Authors: Finegold S M , Ingram-Drake L , Gee R , Reinhardt J , Edelstein M A , MacDonald K , Wexler H
Published: June 2012

Twelve healthy young male subjects received either cefixime, a new oral cephalosporin (CL 284,635), or cefaclor (six subjects on each drug) orally for 2 weeks. In the case of cefixime, single daily doses of 400 mg were taken; with cefaclor, the dosage was 250 mg three times daily. Modest changes in the fecal flora were noted in both drug groups, but the changes were of different types. In the case of cefixime, there was more of an impact on the indigenous flora, and in the case of cefaclor, there was more ingrowth of new flora. With cefixime, Enterobacteriaceae were usually decreased (the decrease in Escherichia coli count was statistically significant), as were counts of clostridia and sometimes Bifidobacterium spp.; the Bacteroides fragilis group was eliminated in one subject. Coincident with these decreases, four subjects had increases in counts of group D streptococci of 3 logs or more. There was new appearance of Clostridium difficile in four subjects and of Staphylococcus aureus in one; four new strains of Enterobacteriaceae appeared. With cefaclor, there was no decrease of E. coli counts; two subjects had elimination of Bifidobacterium spp. There was little change in counts of group D streptococci. On the other hand, there were 13 new strains of Enterobacteriaceae, two of S. aureus, and three of C. difficile.
Biological activity of analogs of guanine and guanosine against American Trypanosoma and Leishmania spp
Authors: Avila J L , Rojas T , Avila A , Polegre M A , Robins R K
Published: June 2012

The growth inhibitory effects of six guanine and guanosine analogs, 3-deazaguanine (compound 1); 3-deazaguanosine (compound 2); 6-aminoallopurinol (compound 3); 9-beta-xylofuranosyl guanine (compound 4); a ribosylated derivative of compound 3, 6-aminopyrazolo(3,4-d)pyrimidin-4-one (compound 5); and 5-aminoformycin B (compound 6), were tested against some pathogenic members of the family of American Trypanosomatidae. Compounds 1 and 2 were highly active against Trypanosoma cruzi, Trypanosoma rangeli, and American Leishmania spp. in in vitro culture forms. Both compounds also showed antiprotozoal activity in T. cruzi-infected mice, with the optimal dose being about 30 mg/kg of body weight per day given as 10 consecutive doses. Compound 3 was the most active compound in vitro, inhibiting all of the American Trypanosomatidae culture forms tested. It was also highly inhibitory in mice that were acutely infected with T. cruzi, with the optimal dose being about 10 mg/kg of body weight per day. Ribosylation of compound 3 resulted in a derivative that showed decreased inhibitory activity on Trypanosomatidae multiplication. Compound 6 was highly inhibitory of in vitro multiplication of American Leishmania and T. rangeli but had no effect on T. cruzi epimastigotes and on mice that were acutely infected with T. cruzi. Compound 4 showed only a slight effect on T. cruzi epimastigotes.
Effect of Haemophilus influenzae infection and moxalactam on platelet function in children
Authors: Kaplan S L , Courtney J T , Kenal K A
Published: June 2012

In a prospective randomized study, children with Haemophilus influenzae type b meningitis received moxalactam or ampicillin or chloramphenicol. Of 41 children, 6 had prolonged bleeding times (greater than 6 min), and 7 of 9 tested had abnormal platelet aggregation at hospital admission. At the end of therapy, no children in the ampicillin-chloramphenicol group, compared with 5 of 22 moxalactam-treated children (23%) (P = 0.08), had prolonged bleeding times (6.5 to 7.5 min). Our data suggest that H. influenzae meningitis and treatment with moxalactam may each have an effect on platelet function in children.
E-0702, a new cephalosporin, is incorporated into Escherichia coli cells via the tonB-dependent iron transport system
Authors: Watanabe N A , Nagasu T , Katsu K , Kitoh K
Published: June 2012

E-0702, a new cephalosporin with a potent antipseudomonal action, was synthesized. In the study of the mode of action of this antibiotic in Escherichia coli, it was found that mutants which acquired resistance to E-0702 were isolated spontaneously and could be shown to be susceptible to its closely related derivatives, E-0702-060 and E-0702-061, and other representative beta-lactam antibiotics. In these mutants, no increased production of beta-lactamase was detectable. No apparent differences between the resistant mutants and the parental strains were observed in the affinity of E-0702 for penicillin-binding proteins. Furthermore, no significant reduction in or loss of both OmpF and OmpC porin proteins in the outer membrane was observed. The mutation was mapped to the tonB gene, which is known to be essential for the iron transport system of bacteria. The bactericidal action of E-0702 was rapidly expressed against iron-starved cells in which the iron transport system was induced, whereas the bactericidal action against iron-supplemented cells was ineffective. It is suggested that E-0702 is incorporated into bacterial cells as a chelator of iron via the tonB-dependent iron transport system, after which its strong and rapid bactericidal action is manifested.
Ciprofloxacin versus vancomycin in the therapy of experimental methicillin-resistant Staphylococcus aureus endocarditis
Authors: Kaatz G W , Barriere S L , Schaberg D R , Fekety R
Published: June 2012

We compared the efficacy of ciprofloxacin with that of vancomycin by using the rabbit model of methicillin-resistant Staphylococcus aureus endocarditis. Endocarditis was treated with ciprofloxacin (25 mg/kg [body weight] intravenously every 8 h) or vancomycin (17.5 mg/kg intravenously every 6 h) for 3 days. Vancomycin and ciprofloxacin were equally efficacious in clearing bacteremia. Both reduced vegetation bacterial counts by 5 log10 CFU/g and renal and splenic bacterial counts by more than 3 log10 CFU/g as compared with untreated control rabbits after 26 h of infection (P less than 0.001). Both antimicrobial agents were able to eradicate the infectious process in an equivalent proportion of animals. No methicillin-resistant S. aureus that was recovered from ciprofloxacin-treated rabbits developed resistance to ciprofloxacin during therapy. Peak concentrations of ciprofloxacin in the sera of rabbits with endocarditis were significantly higher than those predicted by single-dose studies in uninfected rabbits. This finding was likely due to changes in the pharmacokinetics of the drug with multiple dosing and in infected versus uninfected rabbits. This study demonstrated that intravenously administered ciprofloxacin is as efficacious as vancomycin is in an in vivo model of a serious systemic methicillin-resistant S. aureus infection.
In vitro activity and beta-lactamase stability of a new penem, CGP 31608
Authors: Neu H C , Chin N X , Neu N M
Published: June 2012

The in vitro activity of CGP 31608, a new penem, against aerobic and anaerobic organisms was evaluated and compared with those of other beta-lactams. CGP 31608 inhibited Escherichia coli, Klebsiella pneumoniae, K. oxytoca, Proteus mirabilis, Citrobacter diversus, and Salmonella, Shigella, Aeromonas, and Yersinia spp. with MICs for 50% of the strains (MIC50s) of 2 to 4 micrograms/ml and MIC90s of 4 micrograms/ml, compared with cefotaxime, ceftazidime, aztreonam, and imipenem MICs of less than 0.25 microgram/ml. MIC90s were 8 micrograms/ml for Enterobacter species and C. freundii, for which other agents had MICs of 32 micrograms/ml, except imipenem, which had equal activity. The MIC90 for Proteus vulgaris, Morganella morganii, Providencia stuartii, and Providencia rettgeri was 8 micrograms/ml, compared with less than 2 micrograms/ml shown by the other agents. Acinetobacter species resistant to other agents except imipenem were inhibited by 4 micrograms/ml, as were Pseudomonas aeruginosa, including piperacillin-, ceftazidime-, and gentamicin-resistant isolates. The MIC for P. cepacia, P. fluorescens, and P. acidovorans was less than or equal to 8 micrograms/ml, but that for P. maltophilia was greater than or equal to 128 micrograms/ml. Hemolytic streptococci A, B, C, G, and F were inhibited by less than 1 micrograms/ml, but the MIC for Streptococcus faecalis was greater than or equal to 32 micrograms/ml. MICs for Staphylococcus aureus methicillin-susceptible and -resistant strains were less than or equal to 1 microgram/ml, as were those for methicillin-susceptible and -resistant S. epidermidis. Bacteroides fragilis and Clostridium species and Fusobacterium spp. were inhibited by less than or equal to 4 micrograms/ml. CGP 31608 was not hydrolyzed by plasmid beta-lactamases TEM-1, TEM-2, SHV-1, PSE-1, OXA-2, PSE-4, or by S. aureus. Chromosomal beta-lactamases of type Ia in Enterobacter cloacae P99 and Morganella morganii, Ic in P. vulgaris, K-1 in K. oxytoca, and Id in P. aeruginosa also did not hydrolyze CGP 31608. It inhibited TEM-1, but the 50% inhibitory concentration was 14.2 micrograms/ml compared with 0.15 micrograms/ml for the P99 enzyme. CGP 31608 induced beta-lactamases in P. aeruginosa, E. cloacae, C. freundii and Providencia rettgeri, but there was no increase in MICs for the isolates and it did not select strains derepressed for beta-lactamase production. Synergy of CGP 31608 and gentamicin was found against 90% P. aeruginosa, 60% Enterobacter cloacae, and 50% Serratia marcescens strains. No synergy was found with rifampin. A postantibiotic effect was found against E. coli.
Therapeutic effects of imipenem-cilastatin on experimental intrauterine infections in rats
Authors: Hashizume T , Komatsu T , Okumoto Y , Ogashiwa M , Kemi M , Takase Z
Published: June 2012

The therapeutic effects of imipenem-cilastatin (MK-0787-MK-791) on experimental intrauterine infections in progesterone-treated virgin rats and postpartum rats were studied. The relative efficacy of imipenem-cilastatin for the treatment of such intrauterine infections was compared with that of cefazolin and ampicillin for the treatment of infections caused by Escherichia coli and Streptococcus faecalis, respectively. Treatment with imipenem-cilastatin significantly inhibited the proliferation of E. coli and S. faecalis in uteri, as compared with the proliferation in untreated controls. Cefazolin failed to affect the E. coli infection. With the S. faecalis infection, ampicillin effectively reduced bacterial growth, as compared with that in untreated controls. However, ampicillin was inferior to and comparable to imipenem-cilastatin in progesterone-treated virgin rats and postpartum rats, respectively. A further experiment with S. faecalis infections in rats made neutropenic by intraperitoneal injection of cyclophosphamide showed that the therapeutic effectiveness of imipenem-cilastatin was superior to that of ampicillin and was not influenced by neutropenia. Our results suggest that imipenem-cilastatin may be a useful agent for the treatment of obstetric and gynecologic infections.
Instability of vancomycin in Infusaid drug pump model 100
Authors: Greenberg R N , Saeed A M , Kennedy D J , McMillian R
Published: June 2012

The implantable Infusaid drug pump model 100 (Shiley Infusaid, Norwood, Mass.) is undergoing trials as a drug delivery system in the treatment of osteomyelitis. This study evaluated the stability of vancomycin (1 mg/ml) incubated at 37 degrees C for 4 weeks in the pump. Both bioassay and high-pressure liquid chromatography data demonstrated a loss of at least 38% of activity over 4 weeks and colloidal precipitation of vancomycin in the pump at the end of the experiment. This study suggests that vancomycin is not stable enough for use in the Infusaid drug pump model 100.
Effect of food on enoxacin absorption
Authors: Somogyi A A , Bochner F , Keal J A , Rolan P E , Smith M
Published: June 2012

Fifteen subjects received a single 400-mg oral dose of enoxacin in the fasting state and after carbohydrate and high-fat meals. The carbohydrate meal delayed the time to peak enoxacin concentration in plasma by an average of 0.92 h. The extent of enoxacin absorption was not altered by food.
Enhanced immune responses in mice treated with penicillin-tetracycline or trimethoprim-sulfamethoxazole when colonized intragastrically with Candida albicans
Authors: Domer J E , Hector R F
Published: June 2012

Immune consequences of gastrointestinal colonization of CD-1 and CBA/J mice with Candida albicans in the presence or absence of continuous antibiotic treatment with penicillin-tetracycline or trimethoprimsulfamethoxazole were investigated. Intubation with C. albicans in the absence of antibiotics resulted in the induction of low but detectable delayed-type hypersensitivity (DTH), demonstrable by footpad testing with a C. albicans wall glycoprotein (GP), and in the stimulation of a moderate level of protective immunity, demonstrable by intravenous (i.v.) challenge. DTH to a membrane extract, BEX, could not be detected in such animals. However, animals colonized in the presence of antibiotics and then inoculated cutaneously prior to being tested for DTH or protective immunity developed significantly enhanced levels of DTH to GP and BEX and were protected to an even greater extent than animals colonized in the absence of antibiotics who were not inoculated cutaneously. The priming effect of colonization, particularly with respect to the antigen GP, was also obvious from an enzyme-linked immunosorbent assay for GP-specific antibody with sera of mice surviving the i.v. challenge, in that GP-specific antibody was present in the highest titers in colonized animals that had been inoculated cutaneously prior to i.v. challenge. While the antibiotics promoted higher levels of colonization, as evidenced by stomach and fecal cultures of intubated mice, antibiotic administration was not necessary for the induction of C. albicans-specific responses. Moreover, contrary to reports in the literature, antibiotic administration had no adverse effect on the immune responses measured. Females were innately more resistant than males to i.v. challenge with C. albicans, but each sex was capable of developing protective immunity of equal intensity in response to colonization or immunization by cutaneous challenge.
Antimicrobial resistance of Campylobacter jejuni and Campylobacter coli with special reference to plasmid profiles of Japanese clinical isolates
Authors: Sagara H , Mochizuki A , Okamura N , Nakaya R
Published: June 2012

A total of 111 clinical isolates of Campylobacter jejuni and 10 clinical isolates of Campylobacter coli were characterized by their susceptibility to nine antimicrobial agents and by their plasmid profiles on agarose gel electrophoresis. All of the C. jejuni isolates were susceptible to chloramphenicol, ciprofloxacin, erythromycin, kanamycin, and nalidixic acid, but 55% were tetracycline resistant. In the 10 C. coli isolates, a high prevalence of multiple-antibiotic resistance was noted. Plasmids were found in 82% of the tetracycline-resistant and 15% of the tetracycline-susceptible C. jejuni isolates. Tetracycline resistance in six randomly selected C. jejuni isolates, which contained 50- or 135-kilobase (kb) plasmids, was transferred by conjugation to a Campylobacter fetus subsp. fetus recipient with recovery of a 50- or a 45-kb plasmid from transconjugants. From one multiple-antibiotic-resistant C. coli isolate, resistance to tetracycline, kanamycin, and chloramphenicol was transferred concomitantly with a 58-kb plasmid, pNR9589. Nonconjugative 98-kb plasmids, pNR9131 and pNR9581, from C. coli isolates with resistance to tetracycline, kanamycin, and erythromycin were shown by cloning experiments to code for at least kanamycin resistance. Restriction digests revealed that 50-kb plasmids from tetracycline-resistant C. jejuni isolates were identical, although plasmids from multiple-antibiotic-resistant C. coli isolates shared partial DNA homology to each other. Cloning of the kanamycin and chloramphenicol resistance genes of pNR9589 into Escherichia coli showed that the two genes are closely linked or clustered. Double-digestion analysis of the fragments encoding the kanamycin resistance of pNR9131, pNR9581, and pNR9589 showed that these three plasmids contain a common fragment related to kanamycin resistance.
Effect of orally administered activated charcoal on vancomycin clearance
Authors: Davis R L , Roon R A , Koup J R , Smith A L
Published: June 2012

Vancomycin is a narrow-spectrum antibiotic that has concentration-dependent efficacy and toxicity. Recent literature indicates that orally administered activated charcoal can enhance the clearance of intravenously administered drugs. To evaluate the effects of activated charcoal on vancomycin clearance, six healthy male volunteers received vancomycin (1 g) intravenously with and without activated charcoal coadministration. In a randomized crossover sequence, subjects were given 50 g of activated charcoal immediately before the vancomycin infusion was begun and 15 g at 2, 4, 6, and 8 h afterwards, or an equal volume of water. Multiple doses of charcoal did not have a statistically significant effect on any pharmacokinetic parameter for vancomycin. Mean control values +/- standard deviation for vancomycin clearance, elimination half-life, and 24-h urinary recovery were 6.4 +/- 1.0 liters/h, 6.6 +/- 1.5 h, and 856 +/- 116 mg, respectively. Mean values for the same parameters were 6.4 +/- 1.0 liters/h, 6.0 +/- 0.9 h, and 897 +/- 130 mg when activated charcoal was given. We conclude that multiple doses of orally administered activated charcoal do not enhance vancomycin clearance in subjects with normal renal function when serum concentrations are within the therapeutic range. The results of this investigation cannot be extrapolated to patients with toxic vancomycin concentrations or renal dysfunction. The use of activated charcoal in these populations warrants further study.
Development of natural and synthetic DNA probes for OXA-2 and TEM-1 beta-lactamases
Authors: Boissinot M , Mercier J , Levesque R C
Published: June 2012

Cloning of a 6.3-kilobase BglII DNA fragment from plasmid R46 permitted the isolation of the OXA-2 beta-lactamase gene. Selected DNA fragments internal and adjacent to the OXA-2 beta-lactamase structural gene were used as probes in homology studies with other plasmid-mediated beta-lactamases. Under conditions of high stringency, no cross hybridization could be detected with DNA probes from within the open reading frame of the OXA-2 structural gene. At a lower stringency, one of two DNA fragments used as probes cross hybridized weakly with the OXA-3 bla gene. Other DNA fragments tested and known to contain sequences flanking the OXA-2 determinant cross hybridized with OXA-3 and PSE-4 plasmid DNA. From the known nucleotide sequence of OXA-2 and TEM-1, we synthesized a series of oligonucleotides corresponding to sequences internal to their respective structural genes. A 12-mer oligonucleotide containing the OXA-2-active-site nucleotide sequences cross hybridized only with OXA-3. All other oligonucleotides tested were found to be specific for their respective OXA-2 or TEM-1 gene. Such beta-lactamase gene probes should facilitate studies of beta-lactamase molecular epidemiology and beta-lactamase gene polymorphism.
"Streptomyces avermitilis" mutants defective in methylation of avermectins
Authors: Schulman M D , Valentino D , Streicher S , Ruby C
Published: June 2012

"Streptomyces avermitilis" mutants defective in the methylation of the avermectins have been isolated and characterized. Four mutant strains, CR-1, CR-2, CR-3, and CR-4, were unable to methylate the oxygen at C5 of the macrolide moiety and produced essentially only the avermectin B components. These four strains lack avermectin B2 O-methyltransferase (B2OMT) activity. Two mutant strains were unable to methylate the oleandrose moiety at the oxygens at C3' and C3'' and produced essentially only demethylavermectin components. One of these mutants, strain CR-5 (derived from wild-type "S. avermitilis"), produced demethylavermectin A and B components and possessed normal B2OMT levels. The other mutant, strain CR-6 (derived from strain CR-1, which lacks B2OMT activity), produced only demethylavermectin B components. Reaction of 3"-O-demethylavermectin B2a and S-adenosylmethionine with either cell extracts or purified B2OMT resulted in the methylation of the oxygen at C5 of the macrolide moiety and yielded only 3''-O-demethylavermectin A2a as the product. These experiments indicate that different enzymes are required for methylation of the macrolide (the oxygen at C5) and the oleandrose (oxygen at C3) and that methylation of the oleandrose occurs before attachment to the macrolide ring.
Effects of ciprofloxacin on eucaryotic pyrimidine nucleotide biosynthesis and cell growth
Authors: Forsgren A , Bredberg A , Pardee A B , Schlossman S F , Tedder T F
Published: June 2012

Several of the new 4-quinolones significantly increase the incorporation of [3H]thymidine into the DNA of mitogen-stimulated human lymphocytes. This study suggests that ciprofloxacin inhibits de novo pyrimidine biosynthesis, thereby resulting in a compensatory increase in the uptake of pyrimidine precursors through salvage pathways, and that additional effects may affect eucaryotic cell growth. Incorporation of deoxyuridine, uridine, and orotic acid as well as thymidine was increased in the presence of ciprofloxacin, one of the antibacterially most active of the new 4-quinolones. In contrast, the uptake was decreased in very high concentrations of the drug. Culture in HAT (hypoxanthine, aminopterine, thymidine) medium, which blocks de novo thymidylate synthesis, abrogated the increase in [3H]thymidine incorporation induced by ciprofloxacin. Ciprofloxacin also failed to increase the uptake of [14C]hypoxanthine or leucine, indicating a selective effect on pyrimidine and not on purine nucleotide biosynthesis. N-(Phosphonacetyl)-L-aspartate, an inhibitor of pyrimidine nucleotide biosynthesis, also increased [3H]thymidine incorporation in phytohemagglutinin-stimulated lymphocytes in a fashion similar to ciprofloxacin. The growth of several cell lines was partially inhibited by ciprofloxacin at 20 micrograms/ml and completely inhibited at 80 to 160 micrograms/ml. Growth inhibition by ciprofloxacin could not be restored by the addition of uridine to the medium. Chromosome breaks, gene amplification, or other genetic alterations could not be detected in human lymphocytes incubated with up to 25 micrograms of ciprofloxacin per ml.
Rapid in vitro metabolic screen for antileprosy compounds
Authors: Franzblau S G , Hastings R C
Published: June 2012

Measurement of intracellular ATP of Mycobacterium leprae after direct in vitro exposure to antimicrobial agents was evaluated as a rapid means of identifying potentially useful therapeutic agents. Nude mouse-derived M. leprae was incubated in an axenic modified Dubos medium in the presence or absence of antimicrobial agents for up to 3 weeks. ATP was then assayed by using the firefly bioluminescence technique. Rifampin, clofazimine, and ethionamide each effected a significantly accelerated rate of ATP decay compared with controls. Dapsone appeared inactive, possibly reflecting a general insensitivity of this system to compounds acting at certain loci. The system appeared suitable for assessing comparative activity of new structural analogs of clofazimine. Other active compounds included erythromycin, minocycline, chloramphenicol, gramicidin, and, to a lesser extent, cycloserine, cephalothin, ciprofloxacin, tetracycline, and gramicidin S. The penicillins, bacitracin, isoniazid, nalidixic acid, trimethoprim, polymyxin B, and griseofulvin were all inactive. The system appears sensitive to agents with various modes of action and may prove useful as a primary screen for antileprosy drugs.