bluuebunny/crossref_metadata_2025 huggingface dataset:
Alpha-(1-3)- and alpha-(1-6)-D-mannose-specific plant lectins are markedly inhibitory to human immunodeficiency virus and cytomegalovirus infections in vitro
Authors: Balzarini J , Schols D , Neyts J , Van Damme E , Peumans W , De Clercq E
Published: June 2012

The alpha-(1-3)-D-mannose- and alpha-(1-6)-D-mannose-specific agglutinins (lectins) from Galanthus nivalis, Hippeastrum hybrid, Narcissus pseudonarcissus, and Listera ovata inhibited infection of MT-4 cells by human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and simian immunodeficiency virus at concentrations comparable to the concentrations at which dextran sulfate (molecular weight, 5,000 [DS-5000]) inhibits these viruses (50% effective concentration, 0.2 to 0.6 microgram/ml). Unlike DS-5000, however, the plant lectins did not inhibit the replication of other enveloped viruses, except for human cytomegalovirus (50% effective concentration, 0.9 to 1.6 microgram/ml). The plant lectins suppressed syncytium formation between persistently HIV-1- or HIV-2-infected HUT-78 cells and uninfected MOLT-4 (clone 8) cells at concentrations that were 5- to 10-fold lower than that required for DS-5000. Unlike DS-5000, however, the plant lectins did not inhibit HIV-1 binding to CD4+ cells. Combination of the plant lectins with DS-5000 led to a potent synergistic inhibition of HIV-1-induced cytopathogenicity in MT-4 cells and syncytium formation between HIV-infected HUT-78 cells and MOLT-4 cells. Our data suggest that alpha-(1-3)-D- and alpha-(1-6)-D-mannose-specific plant lectins interfere with an event in the HIV replicative cycle that is subsequent to the attachment of the virions to the cells (i.e., the fusion process).
Comparison of the effects of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo
Authors: van Ogtrop M L , Mattie H , Guiot H F , van Strijen E , Sekh B R , van Furth R
Published: June 2012

A study was performed to investigate the pharmacodynamics of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo. The in vitro concentration-effect relationships were determined in short-term growth experiments. The in vivo dose-effect relationships were determined in an experimental thigh muscle infection in irradiated mice. In this model, E. coli was injected into one thigh muscle and K. pneumoniae was injected into the other. Throughout these experiments aztreonam was administered subcutaneously and tigemonam was administered orally. For analysis of the antibacterial pharmacodynamics, the following parameters were determined: the maximum effect as a parameter for efficacy, the 50% effective concentration (or dose) as a parameter for potency, and the slope of the concentration-effect relationship. To assess the relationship between the concentration of the antibiotic and the antibacterial effect in vivo, the pharmacokinetics of the two drugs in the plasma of mice were determined as well. The maximum in vitro and in vivo effects of aztreonam and tigemonam against both bacteria did not differ substantially. However, both drugs killed E. coli more effectively than K. pneumoniae, indicating that the maximum in vitro effect of these drugs against E. coli was higher than that against K. pneumoniae. The maximum in vivo effect of both drugs against E. coli was similar to that against K. pneumoniae. Furthermore, in vitro aztreonam was about twice as potent as tigemonam, but in vivo the reverse was the case. These findings were explained by pharmacokinetic differences between subcutaneously administered aztreonam and orally administered tigemonam, because concentrations of tigemonam in plasma remained at microbiologically active concentrations longer than those of aztreonam did.
Relationship between the Clostridium perfringens catQ gene product and chloramphenicol acetyltransferases from other bacteria
Authors: Bannam T L , Rood J I
Published: June 2012

The nucleotide sequence of the Clostridium perfringens chloramphenicol acetyltransferase (CAT)-encoding resistance determinant, catQ, was determined. An open reading frame encoding a protein of 219 amino acids with a molecular weight of 26,014 was identified. Although catQ was expressed constitutively, sequences similar in structure to those found upstream of inducible cat genes were observed. The catQ gene was distinct from the C. perfringens catP determinant. The deduced CATQ monomer had considerable amino acid sequence conservation compared with CATP (53% similarity) and other known CAT proteins (39 to 53%). Phylogenetic analysis revealed that the CATQ monomer was as closely related to CAT proteins from Staphylococcus aureus and Campylobacter coli as it was to CAT monomers from the clostridia.
Susceptibility of Neisseria gonorrhoeae to cefpodoxime: determination of MICs and disk diffusion zone diameters
Authors: Fekete T , Woodwell J , Cundy K R
Published: June 2012

We studied the susceptibilities of 77 strains of Neisseria gonorrhoeae to four antibiotics: cefpodoxime, ceftriaxone, penicillin, and tetracycline. All strains were susceptible to ceftriaxone. Cefpodoxime MICs (range, 0.001 to 0.125 micrograms/ml) were parallel to and approximately four times those of ceftriaxone, and all strains will probably be considered susceptible to cefpodoxime. Disk diffusion zone diameters for cefpodoxime ranged from 35 to 57 mm. Of the strains, 32% were penicillin resistant and 51% were tetracycline resistant (MIC, greater than or equal to 2 micrograms/ml). Susceptibility measurements were consistent for disk diffusion zone diameter and MIC, with an overall agreement of 215 of 225 (96%) for ceftriaxone, penicillin, and tetracycline combined. On the basis of these in vitro data, cefpodoxime should be evaluated in the treatment of gonorrhea.
SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis
Authors: Lam C , Schütze E , Hildebrandt J , Aschauer H , Liehl E , Macher I , Stütz P
Published: June 2012

SDZ MRL 953, a new synthetic monosaccharidic lipid A, was investigated in vitro and in vivo for immunopharmacological activities. In experimental models of microbial infections, the compound was highly protective when it was administered prophylactically either once or three times to myelosuppressed or immunocompetent mice. The 50% effective doses of SDZ MRL 953 varied with the infectious agents and the route of its administration. In all cases, the 50% effective doses were about 10(3) times higher than those obtained with endotoxin from Salmonella abortus equi. SDZ MRL 953 was, however, less toxic than lipopolysaccharide by a factor of 10(4) to greater than 7 x 10(5) times in galactosamine-sensitized mice. The compound was also an effective inducer of tolerance to endotoxin. Hence, repeated dosing with the compound induced a transient resistance (greater than or equal to 1 week) to lethal challenges with endotoxin. In vitro, the compound was devoid of intrinsic antimicrobial activity, but it moderately induced the release of cytokines from monocytes and primed human neutrophils for the enhanced production of reactive oxygen metabolites in response to a soluble stimulus. The results presented here suggest that SDZ MRL 953 may be useful in a clinical setting for enhancing resistance to infections, particularly in patients undergoing myelosuppressive chemotherapy or irradiation, and for the prophylaxis of endotoxin shock.
Resistance to pefloxacin in Pseudomonas aeruginosa
Authors: Michea-Hamzehpour M , Lucain C , Pechere J C
Published: June 2012

Mechanisms of resistance to pefloxacin were investigated in four isogenic Pseudomonas aeruginosa strains: S (parent isolate; MIC, 2 micrograms/ml), PT1 and PT2 (posttherapy isolates obtained in animals; MICs, 32 and 128 micrograms/ml, respectively), and PT2-r (posttherapy isolate obtained after six in vitro subpassages of PT2; MIC, 32 micrograms/ml). [2-3H]adenine incorporation (indirect evidence of DNA gyrase activity) in EDTA-permeabilized cells was less affected by pefloxacin in PT2 and PT2-r (50% inhibitory concentration, 0.27 and 0.26 microgram/ml, respectively) than it was in S and PT1 (50% inhibitory concentration, 0.04 and 0.05 microgram/ml, respectively). Reduced [14C]pefloxacin labeling of intact cells in strains PT1 and PT2 correlated with more susceptibility to EDTA and the presence of more calcium (P less than 0.05) and phosphorus in the outer membrane fractions. Outer membrane protein analysis showed reduced expression of protein D2 (47 kDa) in strains PT1 and PT2. Other proteins were apparently similar in all strains. The addition of calcium chloride (2 mM) to the sodium dodecyl sulfate-solubilized samples of outer membrane proteins, before heating and Western blotting, probed with monoclonal antibody anti-OmpF showed electrophoretic mobility changes of OmpF in strains PT1 and PT2 which were not seen in strain S. Calcium-induced changes were reversed with ethyleneglycoltetraacetate. Decreased [14C]pefloxacin labeling was further correlated with an altered lipopolysaccharide pattern and increased 3-deoxy-D-mannooctulosonic acid concentration (P less than 0.01). These findings suggested that resistance to pefloxacin is associated with altered DNA gyrase in strain PT2-r, with altered permeability in PT1, and with both mechanisms in PT2. The decreased expression of protein D2 and the higher calcium and lipopolysaccharide contents of the outer membrane could be responsible for the permeability deficiency in P. aeruginosa.
Mechanisms of quinolone resistance in a clinical isolate of Escherichia coli highly resistant to fluoroquinolones but susceptible to nalidixic acid
Authors: Moniot-Ville N , Guibert J , Moreau N , Acar J F , Collatz E , Gutmann L
Published: June 2012

Two associated resistance mechanisms were found in a nalidixic acid-susceptible (4 micrograms/ml) but fluoroquinolone-resistant (8 to 16 micrograms/ml) strain of Escherichia coli Q2 selected under norfloxacin therapy. As compared with the susceptible E. coli Q1 isolated before treatment, changes in outer membrane proteins and lipopolysaccharides in Q2 were associated with a 1.5- to 3-fold decrease in the uptake of fluoroquinolones but not nalidixic acid. A 50% inhibition of DNA synthesis in toluene-permeabilized cells of the resistant strain E. coli Q2 required up to 500-fold increased quantities of fluoroquinolones, whereas such inhibition was obtained in both E. coli Q1 and Q2 with similar amounts of nalidixic acid. Selection from E. coli Q1 on norfloxacin of one-step resistant mutants resembling E. coli Q2 was unsuccessful. From these results we infer that a decrease in outer membrane permeability, associated with a peculiar alteration of the DNA gyrase, was responsible for the unusual quinolone resistance phenotype of E. coli Q2.
Effects of roxithromycin on fecal bacteria in human volunteers and resistance to colonization in gnotobiotic mice
Authors: Pecquet S , Chachaty E , Tancrède C , Andremont A
Published: June 2012

The ecological impact of roxithromycin given orally at 300 mg/day on the intestinal floras in six human volunteers was studied. The resulting fecal concentrations of active roxithromycin were in the range of 100 to 200 micrograms/g of feces. Consecutive modifications in the composition of the fecal floras were limited to a decrease in counts of total members of the family Enterobacteriaceae. The rest of the intestinal floras, including the predominant anaerobic floras, changed little. No overgrowth of Pseudomonas aeruginosa, staphylococci, fungi, or highly erythromycin-resistant strains of the family Enterobacteriaceae was observed. The strains of Enterobacteriaceae and of anaerobes isolated during treatment were not markedly more resistant to roxithromycin than those isolated before treatment started. Changes in intestinal resistance to colonization by exogenous microorganisms in gnotobiotic mice inoculated with human fecal flora were studied and were also found to be minimal. The impact of oral roxithromycin on the intestinal microbiota appears to be weaker than that previously observed with oral erythromycin, perhaps because the concentrations of roxithromycin in the feces were lower than those previously found for erythromycin.
In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci, and enterococci
Authors: Fass R J
Published: June 2012

The in vitro activity of RP 59500, a semisynthetic pristinamycin, was compared with the activities of vancomycin, oxacillin, ampicillin, gentamicin, ciprofloxacin, and rifampin against five Staphylococcus species, five Streptococcus species, and four Enterococcus species. For staphylococci, MICs were 0.13 to 1 microgram/ml and the MICs for 90% of the strains tested (MIC90s) were 0.13 to 0.5 microgram/ml; there were no differences between oxacillin-susceptible and -resistant strains. For streptococci, MICs were 0.03 to 4 micrograms/ml and MIC90s were 0.25 to 2 micrograms/ml; viridans group streptococci were the least susceptible streptococci. For enterococci, MICs were 0.25 to 32 micrograms/ml and MIC90s were 2 to 4 micrograms/ml; Enterococcus faecalis was the least susceptible. Vancomycin was the only comparative drug with consistent activity against all species of gram-positive cocci. With RP 59500, raising the inoculum 100-fold, lowering the pH of cation-adjusted Mueller-Hinton broth to 5.5, or omitting cation supplementation had little effect on MICs, but 50% serum increased MICs 2 to 4 dilution steps. The differences between MBCs and MICs were greater for staphylococci and enterococci than for streptococci. Time-kill studies with 24 strains indicated that RP 59500 concentrations 2-, 4-, and 16-fold greater than the MICs usually killed bacteria of each species at similar rates; reductions in CFU per milliliter were less than those observed with oxacillin or vancomycin against staphylococci and less than those observed with ampicillin against enterococci. RP 59500 antagonized the bactericidal activities of oxacillin and gentamicin against Staphylococcus aureus ATCC 29213 and that of ampicillin against E. faecalis ATCC 29212. Against the latter, combination with gentamicin was indifferent. RP 59500 has a broad spectrum of in vitro activity against gram-positive cocci; combining it with other drugs is not advantageous.
Activities of two new teicoplanin amide derivatives (MDL 62211 and MDL 62873) compared with activities of teicoplanin and vancomycin against 800 recent staphylococcal isolates from France and the United States
Authors: Jones R N , Goldstein F W , Zhou X Y
Published: June 2012

MDL 62211 is the amide derivative of the teicoplanin complex and MDL 62873 is a more focused amide derivative of the teicoplanin A2-2 peak. Each investigational compound had nearly identical activity and was 2- to 16-fold more active than teicoplanin or vancomycin. The MDL 62873 MICs for 90% of the strains tested were as follows: Staphylococcus aureus, oxacillin susceptible, 0.12 micrograms/ml; S. aureus, oxacillin resistant, 0.25 micrograms/ml; coagulase-negative staphylococci (CNS), oxacillin susceptible, 0.25 micrograms/ml; and CNS, oxacillin resistant, 2 micrograms/ml. CNS isolates from France were generally more susceptible than those tested in the United States. Teicoplanin-resistant U.S. isolates were usually Staphylococcus haemolyticus (1.8% of all tested strains), for which MICs ranged from 32 to greater than 128 micrograms/ml. MDL 62873 was not active against the Bacteroides fragilis group but was generally effective against gram-positive anaerobic strains.
Susceptibility of anaerobic bacteria to BAY v 3522
Authors: Nord C E , Rylander M , Norrby S R
Published: June 2012

The activity of BAY v 3522 against 340 strains of anaerobic bacteria was determined by an agar dilution method. Its activity was compared with those of amoxicillin, amoxicillin-clavulanate, cefaclor, cefadroxil, cefoxitin, cefuroxime, cephalexin, clindamycin, doxycycline, and metronidazole. BAY v 3522, amoxicillin-clavulanate, cefoxitin, clindamycin, and metronidazole were the most active agents tested. On the basis of these results, BAY v 3522 appears to have an antibacterial activity that warrants further investigation in clinical trials.
Ceftazidime as monotherapy or combined with teicoplanin for initial empiric treatment of presumed bacteremia in febrile granulocytopenic patients
Authors: Nováková I , Donnelly J P , De Pauw B
Published: June 2012

In a prospective randomized study, 120 febrile, granulocytopenic patients received as initial therapy ceftazidime with or without teicoplanin. At the onset of fever, patients had no obvious infectious focus. For 103 assessable episodes, initial bacteremias were detected in 18 of 51 patients (35%) given ceftazidime and 20 of 52 patients (38%) given the combination; 13 and 17 bacteremias caused by gram-positive bacteria occurred in these groups, respectively. There was no difference in terms of the final response (25 of 51 patients [49%] treated with ceftazidime alone versus 33 of 52 patients [63%] given the combination), and the morbidity was comparable for both treatment groups. The duration of fever and of total antibiotic therapy were similar in both groups. Initial therapy was modified in 26 patients (51%) treated with ceftazidime, with 20 surviving the infection, and in 19 patients (37%) treated with the combination, with 15 surviving. Persistent fever was the main reason for changing treatment, and no patient died of a gram-positive infection. Subsequent infective events occurred in 16 patients (31%) given ceftazidime and in 25 patients (48%) given the combination. Lung infiltrates developed in 12 and 13 patients, respectively, but more new infections occurred in the combination group. Allergic skin reactions were also more frequent in this group. Thus, while teicoplanin provides simple, reliable, and safe treatment of patients with presumed gram-positive infections, it is not useful when given empirically to this patient population, and treatment may result in more infective complications and adverse events.
Beta-Lactam-beta-lactamase-inhibitor combinations are active in experimental endocarditis caused by beta-lactamase-producing oxacillin-resistant staphylococci
Authors: Hirano L , Bayer A S
Published: June 2012

Optimal therapeutic strategies for serious infections caused by borderline and heterotypic oxacillin-resistant Staphylococcus aureus (BORSA and ORSA) strains have not been fully characterized. Recent evidence suggests that the dominant penicillin-binding protein of ORSA strains (PBP 2a) shows good affinity for ampicillin and that these strains commonly produce beta-lactamase. Therefore, we compared the in vivo efficacy of the combination of ampicillin plus sulbactam with that of vancomycin against ORSA strains. Also, the moderate resistance of BORSA strains appears to be attributable mainly to the hyperproduction of beta-lactamase. Therefore, we also studied the in vivo efficacy of ampicillin plus sulbactam against such organisms. Experimental aortic endocarditis was induced in rabbits by the following three strains: beta-lactamase-producing BORSA strain VP-986, beta-lactamase-producing ORSA strain 67-0, and its beta-lactamase-negative clone. In animals with BORSA endocarditis, ampicillin plus sulbactam and oxacillin were highly effective in reducing mean intravegetation bacterial densities, with each being significantly better than either ampicillin alone or no therapy. In animals with endocarditis caused by the beta-lactamase-producing ORSA strain, ampicillin plus sulbactam was significantly better at reducing mean vegetation bacterial densities than the other regimens. For endocarditis caused by the beta-lactamase-negative ORSA clone, ampicillin was better than vancomycin in reducing mean intravegetation bacterial densities. These data show that infections caused by beta-lactamase-producing BORSA strains respond therapeutically in a manner similar to that of infections caused by oxacillin-susceptible strains, with both oxacillin and ampicillin plus sulbactam being highly efficacious. Moreover, high-dose ampicillin treatment strategies were effective in the therapy of ORSA endocarditis; this efficacy is presumably related to the relatively high affinity profile of this compound (compare with that of oxacillin) for the functionally dominant ORSA PBP 2a.
Antiproliferative effects and mechanism of action of ICI 195,739, a novel bis-triazole derivative, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi
Authors: Urbina J A , Lazardi K , Aguirre T , Piras M M , Piras R
Published: June 2012

The in vitro antiproliferative effects of ICI 195,739, a recently developed bis-triazole derivative (T. Boyle, D. J. Gilman, M. B. Gravestock, and J. M. Wardleworth, Ann. N.Y. Acad. Sci. 544:86-100, 1988; J. F. Ryley, S. McGregor, and R. G. Wilson, Ann. N.Y. Acad. Sci. 544:310-328, 1988), on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi and some aspects of its mechanism of action are described. Despite previous claims that triazole compounds act on susceptible organisms by essentially the same mechanism demonstrated for the imidazole compounds, i.e., by interfering with the synthesis of ergosterol at the level of the cytochrome P-450-dependent C-14 demethylation of lanosterol, our results indicate that ICI 195,739 acts on T. cruzi epimastigotes by a dual mechanism which involves blockade of ergosterol byosynthesis and a second, still-unidentified target whose alteration leads to immediate growth arrest. Although ICI 195,739 blocks ergosterol biosynthesis at the level of C-14 lanosterol demethylation, as shown by gas-liquid and thin-layer chromatography, growth arrest in ICI 195,739-treated cells is not related to the depletion of the endogenous ergosterol pool, contrary to what was previously found for ketoconazole, the reference compound among antifungal and antiprotozoal azole derivatives. Consistent with this observation is the fact that the concentration of ICI 195,739 required to inhibit de novo synthesis of ergosterol in epimastigotes by 50% is 60 nM, which is essentially identical to that previously found for ketoconazole under identical conditions, while the minimum concentration required to produce complete growth inhibition is 0.1 microM, which is 300 times lower than that of ketoconazole. With respect to the intracellular amastigote form proliferating inside vertebrate (Vero) cells, 10 nM is sufficient to eradicate the parasite completely in 96 h, with no effects on the host cells; this concentration is identical to that previously found for ketoconazole. Growth inhibition and morphological alterations induced by ketoconazole can be reserved by exogenously added ergosterol but not by cholesterol; for ICI 195, 739, neither sterol is capable of reserving the drug effects. Contrary to what was observed for ketoconazole, the in vitro antiproliferative effects of ICI 195, 739 on both forms of the parasite are not potentiated by the simultaneous presence of terbinafine, an allylamine which blocks ergosterol production by the parasite at a different level of the sterol biosynthetic pathway. These results, together with those of an accompanying study of the ultrastructural alterations induced by the drug, strongly support the notion that ICI 195, 739 acts on T. cruzi by a novel combination of biochemical and cellular effects, which could explain its extraordinary potency in vivo against the parasite.
Ultrastructural alterations induced by ICI 195,739, a bis-triazole derivative with strong antiproliferative action against Trypanosoma (Schizotrypanum) cruzi
Authors: Lazardi K , Urbina J A , de Souza W
Published: June 2012

The ultrastructural alterations induced in vitro by ICI 195,739, a recently developed bis-triazole derivative with potent antiproliferative effects on Trypanosoma (Schizotrypanum) cruzi, are reported. On epimastigotes, the triazole at its minimum growth-inhibitory concentration (0.1 microM) produced immediately (within 24 h) gross alterations in the organization of chromatin and the appearance of large electron-dense granules; at this time, many cells were binucleated, indicating a blockade in cytokinesis. At later times (120 h), mitochondrial swelling, a characteristic effect reported previously for the dioxolane-imidazole ketoconazole when the performed ergosterol pool is depleted, was the predominant effect and led to cell lysis. In amastigotes proliferating in Vero cells, the drug at 10 nM produced mitochondrial swelling, autophagic vacuoles, and massive alterations of the plasma membrane, leading to complete parasite destruction after 96 h of incubation of the infected monolayers with the drug. The results support previous conclusions that ICI 195,739 has a dual mechanism of action against T. cruzi, involving blockade of ergosterol biosynthesis and a direct effect on cell division which cannot be reversed by addition of exogenous ergosterol.
Loracarbef versus cefaclor in the treatment of urinary tract infections in women
Authors: Iravani A
Published: June 2012

In a double-blind, prospective, randomized study, 108 college women with acute urinary tract infections were treated for 7 days with either loracarbef (LY163892) at 200 mg once daily (n = 53) or cefaclor at 250 mg three times daily (n = 55). The cure rates at 5 to 9 days after treatment in the loracarbef and cefaclor groups were 96 and 90%, respectively. Both loracarbef and cefaclor are safe, well tolerated, and effective in the treatment of urinary tract infections in women.
Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis
Authors: Fattal E , Rojas J , Youssef M , Couvreur P , Andremont A
Published: June 2012

The tissue distribution of ampicillin entrapped in liposomes was studied in normal noninfected mice and showed that ampicillin concentrated mostly in the liver and spleen. Liposomate ampicillin was significantly more effective than free ampicillin in reducing splenic and hepatic bacterial counts in C57BL/Ka nude mice chronically infected with Listeria monocytogenes EGD. It was also significantly more effective than free ampicillin in reducing mortality in C57BL/6 mice acutely infected with Salmonella typhimurium C5. Comparison of the results with those previously obtained in the same experimental models with the same amounts of ampicillin bound to polyisohexylcyanoacrylate nanoparticles showed that liposomes were more effective than nanoparticles (M. Youssef, E. Fattal, M. J. Alonso, L. Roblot-Treupel, J. Sauzières, C. Tancrède, A. Omnès, P. Couvreur, and A. Andremont, Antimicrob. Agents Chemother. 32:1204-1207, 1988) in targeting ampicillin to the spleen but were less effective than nanoparticles in targeting ampicillin to the liver and reducing mortality in acute salmonellosis.
Effect of clindamycin on pneumonia from reactivation of Toxoplasma gondii infection in mice
Authors: Filice G A , Pomeroy C
Published: June 2012

Clindamycin was used to treat the reactivation of a chronic Toxoplasma gondii infection in mice. Clindamycin reduced mortality by 44% when used prophylactically (P less than 0.001) but appeared to be less effective when used to treat clinically apparent reactivation. Further studies should be conducted to establish the efficacy of clindamycin for the treatment of toxoplasmosis in humans.
MICs and MBCs of chemotherapeutic agents against Renibacterium salmoninarum
Authors: Bandín I , Santos Y , Toranzo A E , Barja J L
Published: June 2012

The efficacies of 21 chemotherapeutic agents for controlling bacterial kidney disease were evaluated. The bactericidal and/or bacteriostatic effects of these drugs were tested against 11 Renibacterium salmoninarum strains with different origins. The most effective compounds displaying both bacteriostatic and bactericidal activity for all the isolates were tetracycline and erythromycin, with MICs ranging from less than 0.62 to 10.95 micrograms/ml for tetracycline and from less than 0.62 to 5.47 micrograms/ml for erythromycin. Whereas tetracycline showed identical MICs and MBCs, erythromycin showed bactericidal effects at concentrations of 5.47 to 21.87 micrograms/ml. Similarly, cefazolin and tiamulin proved to be very effective bactericidal compounds against the majority of R. salmoninarum isolates, with MBCs for 90% of the strains tested of 21.87 and 10.95 micrograms/ml, respectively. Neither nitrofuranes, quinolones, nor sulfonamides showed inhibitory effects on the growth of the strains.
Tetracycline resistance heterogeneity in Enterococcus faecium
Authors: Bentorcha F , De Cespédès G , Horaud T
Published: June 2012

The tetracycline (Tet) determinants, which encode resistance either to tetracyclines without minocycline (Tcr) or to tetracyclines including minocycline (Tcr-Mnr), of 30 wild-type clinical isolates of Enterococcus faecium were identified and localized. The Tet determinants were transferred by conjugation into a plasmid-free Enterococcus faecalis recipient at frequencies of 10(-6) to 10(-9) transconjugants per donor, as follows: Tcr, 6 strains; Tcr-Mnr, 14 strains; both Tcr and Tcr-Mnr, 6 strains; no detectable transfer, 4 strains. Classes L (Tcr phenotype) and M and O (Tcr-Mnr phenotype) of the Tet determinants were identified by DNA-DNA hybridization experiments. The Tet L determinant was plasmid-borne in 18 strains and was chromosomal in 2 strains. Tet M was chromosomal in 27 strains and plasmid-borne (pIP1534) in 1 strain; pIP1534 also carried Tet L. Tet M was located on Tn916-like elements in 22 strains and on a Tn916-modified element in 1 strain. Tet O was detected in only one strain in which it was plasmid-borne. Both Tet L and Tet M determinants were carried by 19 strains. One strain carried, in addition to chromosomal nonconjugative Tet L and Tet M determinants, a conjugative Tcr-Mnr marker which did not correspond to any Tet determinant tested in this study. These results attest to the genetic complexity of tetracycline resistance in E. faecium strains.
Comparative in vitro antibacterial activity of sparfloxacin (AT-4140; RP 64206), a new quinolone
Authors: Visser M R , Rozenberg-Arska M , Beumer H , Hoepelman I M , Verhoef J
Published: June 2012

The in vitro activity of sparfloxacin (AT-4140; RP 64206), a new fluoroquinolone, was compared with those of 10 other agents against 1,222 clinical isolates. Sparfloxacin and ciprofloxacin were the most active quinolones against members of the family Enterobacteriaceae and nonfermenting gram-negative bacilli; sparfloxacin had superior activity against gram-positive cocci in comparison with the activities of ciprofloxacin and the other quinolones tested (norfloxacin, lomefloxacin, and pefloxacin). Among the inhibited strains, several were resistant to the tested beta-lactam antibiotics or to aminoglycosides. The activity of sparfloxacin was not influenced by the medium that was used; lowering of the pH to 5 had a marked effect on the MICs for two strains each of Enterobacter cloacae and Pseudomonas aeruginosa and one strain each of Escherichia coli and Staphylococcus aureus; the MBC of sparfloxacin was within 1 to 2 dilution steps of the MIC for the strains that were tested.
Nucleotide sequence of the aacC3 gene, a gentamicin resistance determinant encoding aminoglycoside-(3)-N-acetyltransferase III expressed in Pseudomonas aeruginosa but not in Escherichia coli
Authors: Vliegenthart J S , Ketelaar-van Gaalen P A , van de Klundert J A
Published: June 2012

A chromosomal gentamicin resistance determinant from Pseudomonas aeruginosa was cloned on a 2.4-kb fragment in the broad-host-range vector pLAFR3. Substrate profiles for eight aminoglycosides at three concentrations showed that resistance was due to aminoglycoside-(3)-N-acetyltransferase III. This enzyme was produced in Pseudomonas strains but not in an Escherichia coli strain bearing the aacC3 gene. Nucleotide sequencing revealed two contiguous open reading frames (ORFs) preceded by a potential promoter and a ribosome-binding site. ORF-1 was 642 bp in length and encoded a protein of unknown function with a molecular mass of 23.9 kDa. ORF-2 was 813 bp in length and encoded a protein of 29.6 kDa. From deletion mutagenesis, in vitro transcription-translation data, and protein analysis of bacterial lysates, it was inferred that this 29.6-kDa protein represents the aminoglycoside-(3)-N-acetyltransferase III enzyme. A polymerase chain reaction with two specific intragenic 20-mer primers was developed to detect the aacC3 gene. A BstEII restriction site in the amplified DNA region was used to demonstrate the specificity of the reaction. Tests of 23 reference strains, which produced 12 different aminoglycoside-modifying enzymes, confirmed the specificities of the primers. The gene proved to be absent from a collection of 50 gentamicin-resistant P. aeruginosa strains selected at random in The Netherlands.
Invalidity for Pseudomonas aeruginosa of an accepted model of bacterial permeability to beta-lactam antibiotics
Authors: Livermore D M , Davy K W
Published: June 2012

The accepted model for the penetration of beta-lactam antibiotics into gram-negative bacteria is that proposed by Zimmermann and Rosselet (Antimicrob. Agents Chemother. 12:368-372, 1977). The model assumes (i) that diffusion of the antibiotic molecules across the outer membrane obeys Fick's law and can be characterized by a permeability constant for any given combination of organism and drug, (ii) that drug hydrolysis within the periplasm obeys Michaelis-Menten kinetics, and (iii) that a steady state is rapidly attained between drug uptake and hydrolysis. The model has allowed accurate prediction of antibiotic MICs for Escherichia coli strains from a knowledge of their beta-lactamase production and permeability characteristics. It has been suggested that the model is inappropriate for Pseudomonas aeruginosa, but attempts to confirm this have been bedevilled by experimental difficulties in estimating permeability coefficients for this species. In the present study, we tested a prediction of the model that the overall resistance of P. aeruginosa transconjugants containing a plasmid-encoded beta-lactamase should continue to depend partly on permeability. Transconjugants with PSE-4 beta-lactamase were constructed in host strains with widely different levels of intrinsic, presumably impermeability-determined resistance. Contrary to the prediction of the model, all the transconjugants developed identical overall levels of resistance to substrate beta-lactams, such as azlocillin and cefoperazone, irrespective of the initial levels of intrinsic resistance of the recipient strains. We conclude that the model is inappropriate for P. aeruginosa, and possible explanations for the organism's behavior are discussed.
Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function
Authors: Pietroski N A , Graziani A L , Lawson L A , Bland J A , Rogers J D , MacGregor R R
Published: June 2012

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.
Modulation of the intestinal flora of mice by treatment with aztreonam and tigemonam
Authors: van Ogtrop M L , Guiot H F , Mattie H , van Strijen E , Sekh B R , van Furth R
Published: June 2012

Oral and parenteral administration of aztreonam and oral administration of tigemonam to conventional mice caused a decrease in the number of aerobic gram-negative rods in the feces. Oral treatment with high doses of aztreonam (greater than or equal to 25 mg/kg/day) and tigemonam (100 mg/kg/day) adversely influenced colonization resistance, whereas oral treatment with lower doses of the monobactams or parenteral treatment with aztreonam did not.
Effect of low-level and intermittent minocycline therapy on the growth of Mycobacterium leprae in mice
Authors: Gelber R H , Siu P , Tsang M , Alley P , Murray L P
Published: June 2012

We evaluated the minimal concentrations of minocycline in the diet and in serum required to inhibit the growth of seven Mycobacterium leprae isolates in mice. Minocycline concentrations of 0.01 and 0.04% in the diet, which resulted in levels in serum of less than or equal to 0.17 and 0.51 microgram/ml, respectively, were consistently and completely inhibitory. Even 0.004% dietary minocycline (levels in serum, less than or equal to 0.08 microgram/ml) partially inhibited five of these strains, while 0.001% minocycline was consistently inactive. For five of these isolates, minocycline at a concentration of 0.04% in the diet given 3 days (Monday, Wednesday, Friday) and 1 day weekly completely inhibited the growth of M. leprae, and minocycline given even 1 day monthly was partially inhibitory for three of these five M. leprae isolates.
Activity of mersacidin, a novel peptide, compared with that of vancomycin, teicoplanin, and daptomycin
Authors: Niu W W , Neu H C
Published: June 2012

Mersacidin, a new peptide antibiotic, was four- to eightfold less active (MIC for 90% of isolates, 8 micrograms/ml) than vancomycin, teicoplanin, or daptomycin against Staphylococcus aureus. Coagulase-negative staphylococci were inhibited by 8 micrograms/ml, and the MICs of mersacidin for hemolytic streptococci and Streptococcus pneumoniae were 4 to 8 micrograms/ml. The mersacidin MICs for anaerobic organisms were as follows: Clostridium perfringens, 4 micrograms/ml; Propionibacterium acnes, 8 micrograms/ml; peptococci, 1 microgram/ml; and peptostreptococci, 8 micrograms/ml. Mersacidin had no activity against members of the family Enterobacteriaceae, Neisseria and Haemophilus species, or Pseudomonas aeruginosa. The size of the inoculum, the pH of the assay (5.5 to 7.5), the type of medium, and the anaerobic conditions had minimal effects on the MICs and MBCs of mersacidin. Overall, mersacidin proved less active than available glycopeptides and peptolides.
Mechanisms of clinical resistance to fluoroquinolones in Enterococcus faecalis
Authors: Nakanishi N , Yoshida S , Wakebe H , Inoue M , Mitsuhashi S
Published: June 2012

About 10% of 100 clinical isolates of Enterococcus faecalis were resistant to greater than or equal to 25 micrograms of norfloxacin, ofloxacin, ciprofloxacin, and temafloxacin per ml. In this study, the DNA gyrase of E. faecalis was purified from a fluoroquinolone-susceptible strain (ATCC 19433) and two resistant isolates, MS16968 and MS16996. Strains MS16968 and MS16996 were 64- to 128-fold and 16- to 32-fold less susceptible, respectively, to fluoroquinolones than was ATCC 19433; MICs of nonquinolone antibacterial agents for these strains were almost equal. The DNA gyrase from ATCC 19433 had two subunits, designated A and B, with properties similar to those of DNA gyrase from other gram-positive bacteria such as Bacillus subtilis and Micrococcus luteus. Inhibition of the supercoiling activity of the enzyme from ATCC 19433 by the fluoroquinolones correlated with their antibacterial activities. In contrast, preparations of DNA gyrase from MS16968 and MS16996 were at least 30-fold less sensitive to inhibition of supercoiling by the fluoroquinolones than the gyrase from ATCC 19433 was. Experiments that combined heterologous gyrase subunits showed that the A subunit from either of the resistant isolates conferred resistance to fluoroquinolones. These findings indicate that an alteration in the gyrase A subunit is the major contributor to fluoroquinolone resistance in E. faecalis clinical isolates. A difference in drug uptake may also contribute to the level of fluoroquinolone resistance in these isolates.
Antimicrobial susceptibility and molecular epidemiology of beta-lactamase-producing, aminoglycoside-resistant isolates of Enterococcus faecalis
Authors: Markowitz S M , Wells V D , Williams D S , Stuart C G , Coudron P E , Wong E S
Published: June 2012

beta-Lactamase-producing (BL+), aminoglycoside-resistant (AR) Enterococcus faecalis is endemic in our hospital, having caused widespread colonization and infection. Suitable therapy for infections caused by these organisms has been problematic. We compared the antimicrobial and bactericidal activities, by broth macrodilution and time-kill methods, of several antibiotics, alone and in combination, against BL+, AR isolates of E. faecalis and determined the transmissibility of antibiotic resistance markers. Ampicillin-sulbactam, imipenem, daptomycin, and ciprofloxacin were the most active antibiotics with MICs for 90% of isolates tested of 2, 1, 2, and 1 microgram/ml, respectively, against inocula of 10(3) and 10(5) CFU/ml. Little inoculum effect was noted with imipenem, vancomycin, daptomycin, or ciprofloxacin, while the addition of sulbactam to ampicillin partially inhibited the effect of the increased inoculum. Penicillin-sulbactam and ampicillin-sulbactam combinations in a 2:1 ratio were most frequently bactericidal (greater than or equal to 3-log10-unit decrease in bacterial titers at 24 h for 13 of 20 isolates), followed by daptomycin (8 of 20 isolates) and ciprofloxacin (2 of 20 isolates). Bactericidal activity was not demonstrated for imipenem or teicoplanin. beta-Lactamase production and aminoglycoside resistance were associated with a 60- to 65-MDa plasmid which was easily transferred to a plasmid-free E. faecalis recipient. The 840-bp beta-lactamase gene probe hybridized to purified plasmid DNA from BL+ donor isolates of E. faecalis and transconjugants but not from BL- isolates. Ampicillin-sulbactam and daptomycin (an investigational antibiotic) seem to be reasonable choices for the empiric therapy of presumed enterococcal infections in hospitals in which BL+, AR E. faecalis strains are isolated. Their use should ideally be supported by tests for bactericidal activity.
Pharmacokinetics and tissue penetration of tazobactam administered alone and with piperacillin
Authors: Wise R , Logan M , Cooper M , Andrews J M
Published: June 2012

The pharmacokinetics of tazobactam (500 mg) administered intravenously alone were compared with the pharmacokinetics of tazobactam coadministered with piperacillin (4 g), and the penetration into an inflammatory exudate in six healthy males was studied. Piperacillin influenced the pharmacokinetics of tazobactam. The mean levels of tazobactam in plasma at 4 h were 0.6 microgram/ml when it was given alone and 1.2 micrograms/ml when it was given with piperacillin (P = 0.0003). The mean total clearances of tazobactam were 203.5 and 134.2 ml/min (P = 0.035) when it was given alone and with piperacillin, respectively There were no significant differences in the elimination half lives, areas under the concentration-time curve from 0 h to infinity, or volumes of distribution. Inflammatory exudate penetration was rapid, and the mean maximum levels of tazobactam attained were 6.4 and 11.3 micrograms/ml when it was given alone or with piperacillin, respectively (P less than 0.06). The mean percent penetration of tazobactam and the area under the concentration-time curve from 0 h to infinity in inflammatory exudate were greater when tazobactam was given with piperacillin. The mean 24-h urinary recoveries of tazobactam were 63.7% +/- 7.9% when it was given alone and 56.8% +/- 2.7% when it was given with piperacillin. The explanation for the differences in the pharmacokinetics of tazobactam when it was administered alone compared with those when it was given with piperacillin was unclear.
Ocular kinetics of pefloxacin after intramuscular administration in albino and pigmented rabbits
Authors: Cochereau-Massin I , Bauchet J , Faurisson F , Vallois J M , Lacombe P , Pocidalo J J
Published: June 2012

We determined the ocular kinetics of pefloxacin, a new fluoroquinolone, when administered by the intramuscular route to albino and pigmented rabbits. In serum of albino rabbits, the area under the concentration-time curve (AUC) for the experimental period was 31.4 +/- 1.07 micrograms.h/ml (mean +/- standard deviation); the AUCs in the aqueous and vitreous humors were high (10.5 +/- 1.90 and 12.4 +/- 3.79 micrograms.h/ml, respectively). Pefloxacin was found in the avascular ocular tissues (30.15 +/- 3.79 micrograms.h/ml in the cornea and 6.98 +/- 1.06 micrograms.h/ml in the lens). In the vascularized tissues, the penetration ratio, defined as tissue AUC/serum AUC, was more than 1. The good intraocular diffusion of pefloxacin might be related to its low molecular weight and to its strong lipophilicity and could explain its clinical efficacy in the treatment of endophthalmitis. In pigmented rabbits, pefloxacin levels were high in the iris (1525 +/- 328 micrograms.h/ml, versus 40.2 +/- 5.08 micrograms.h/ml in albino rabbits) and chorioretina (2600 +/- 422 micrograms.h/ml, versus 48.3 +/- 7.52 micrograms.h/ml in albino rabbits), suggesting that it binds to the pigmentary apparatus.
Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin
Authors: Counter F T , Ensminger P W , Preston D A , Wu C Y , Greene J M , Felty-Duckworth A M , Paschal J W , Kirst H A
Published: June 2012

Dirithromycin is a 9-N-11-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.