Antimicrobial Agents and Chemotherapy

Baqar, S; Pacheco, N D; Rollwagen, F M

doi: 10.1128/AAC.pmid: 8109936

The effect of oral recombinant interleukin (rIL) treatment on the course of Campylobacter jejuni infection and the development of mucosal immunity in mice was investigated. rIL-2, rIL-5, and rIL-6 were administered to mice at 24 and 6 h before infection and at 0, 24, and 48 h after infection with C. jejuni HC, and the subsequent development of an immune response and intestinal colonization resistance were determined. In this model, orally administered cytokines retained their biological activities with no apparent side effects. Following infection, initial bacterial counts in fecal samples collected from cytokine-treated and untreated mice were similar. However, within 48 h of infection a greater than 3-log-unit reduction in the number of C. jejuni shed in the feces was found for rIL-6-treated animals. Colonization levels were similarly reduced in rIL-5-treated mice, although the rate of clearance was somewhat slower. In contrast, rIL-2 treatment had no significant effect on colonization levels compared with that in controls. Oral rIL-6 treatment was also associated with enhanced intestinal and systemic Campylobacter-specific immunoglobulin A responses compared with those observed in either rIL-5- or rIL-2-treated animals. Upon rechallenge, initial colonization in all cytokine-treated groups was approximately 2 log units lower than that in controls. However, local infection was controlled only in rIL-2-treated mice over time. rIL-5 and rIL-6 treatment had only a marginal effect on colonization resistance following rechallenge. On the basis of these results, it appears that rIL-5 or rIL-6 may function to modulate the induction and/or expression of anti-C. jejuni immunity through different mechanisms. Antimicrob Agents Chemother. 1993 December; 37(12): 2688-2692

Aoki, Y; Yoshihara, F; Kondoh, M; Nakamura, Y; Nakayama, N; Arisawa, M

doi: 10.1128/AAC.pmid: 8109933

Ro 09-1470 is a new antifungal agent that belongs to a series of compounds characterized by a tetrahydropyran skeleton with glycine and alkenyl side chains and that inhibits P-450 lanosterol C-14 demethylase (P-450(14DM)) of fungi (Y. Aoki, T. Yamazaki, M. Kondoh, Y. Sudoh, N. Nakayama, Y. Sekine, H. Shimada, and M. Arisawa, J. Antibiot. 45:160-170, 1992; S. Matsukuma, T. Ohtsuka, H. Kotaki, H. Sawairi, T. Sano, K. Watanabe, N. Nakayama, Y. Itezono, M. Fujiu, N. Shimma, K. Yokose, and T. Okuda, J. Antibiot. 45:151-159, 1992). We have studied the compound's mode of interaction with fungal P-450(14DM) and its selectivity for the fungal versus mammalian P-450 enzymes. Ro 09-1470 bound to the Saccharomyces cerevisiae P-450(14DM) by coordinating to the heme with one-to-one stoichiometry. Unlike the azole compounds, it interacted with both ferric and ferrous heme. It was active also against the P-450(14DM) of Candida albicans. Ro 09-1470 preferentially inhibited the yeast P-450(14DM), showing a 50% inhibitory concentration (IC50) of 0.47 to approximately 1.1 microM, which is much lower than the IC50s for rat hepatic P-450s catalyzing cholesterol biosynthesis (IC50 = 341 microM), p-nitroanisol O-demethylation (> 1,000 microM), aniline hydroxylation (> 1,000 microM), and aminopyrine N-demethylation (920 microM). The degree of selectivity for yeast P-450 was higher than that of ketoconazole. Antimicrob Agents Chemother. 1993 December; 37(12): 2662-2667

Maurin, M; Raoult, D

doi: 10.1128/AAC.pmid: 8109928

The in vitro bacteriostatic activity of clarithromycin, a new macrolide derivative, against Rickettsia rickettsii, Rickettsia conorii, and "Rickettsia israeli" was determined by the plaque assay and the dye uptake assay. Both bacteriostatic and bactericidal activities of clarithromycin against the Nine Mile, Q212, Priscilla, and ME9 strains of Coxiella burnetti were evaluated by using three cell culture systems. Clarithromycin showed improved antibacterial activity compared with that of erythromycin. A bacteriostatic activity was obtained at concentrations below the reported maximum concentration of clarithromycin in human serum (about 4 micrograms/ml) for all tested rickettsiae. MICs ranged from 1 to 2 micrograms/ml for the three Rickettsia species and from 1 to 4 micrograms/ml for the C. burnetti strains. No bactericidal activity against C. burnetti was obtained when clarithromycin was used at 4 micrograms/ml. Antimicrob Agents Chemother. 1993 December; 37(12): 2633-2637

Trieu-Cuot, P; de Cespedes, G; Bentorcha, F; Delbos, F; Gaspar, E; Horaud, T

doi: 10.1128/AAC.pmid: 8109922

An assay based on the utilization of degenerate primers that enable enzymatic amplification of an internal fragment of cat genes known to be present in gram-positive cocci was developed to identify the genes encoding chloramphenicol resistance in streptococci and enterococci. The functionality of this system was illustrated by the detection of cat genes belonging to four different hydridization classes represented by the staphylococcal genes catpC221, catpC194, catpSCS7, and the clostridial gene catP, and by the characterization of a new streptococcal cat gene designated catS. A sequence related to the clostridial catQ gene, which was present in one streptococcal strain, was not detected by this assay. These results reveal that these six cat genes account for chromosomal-borne chloramphenicol resistance in 12 group A, B, and G streptococci tested. By contrast, only three of these six cat genes (catpC221, catpC194, and catpSCS7) were detected on the 10 enterococcal plasmids studied here that encode resistance to chloramphenicol. Antimicrob Agents Chemother. 1993 December; 37(12): 2593-2598

Sumita, Y; Fukasawa, M

doi: 10.1128/AAC.pmid: 8109947

Pseudomonas aeruginosa PAO1 showed increased phenotypic resistance to imipenem, panipenem, and biapenem specifically in the presence of salicylate. The antipseudomonal activity of carbapenems was reduced in proportion to the concentration of salicylate. This resistance was transient and nonheritable. The synthesis of the outer membrane protein D2 (OprD or OprD2) in P. aeruginosa PAO1 was inhibited by 4 to 32 mM salicylate in the bacterial growth medium, whereas no changes in any other outer membrane proteins were observed. These results indicate that salicylate suppresses the synthesis of OprD and therefore reduces the antipseudomonal activity of carbapenems. Under these conditions, one carbapenem--meropenem--is still active against P. aeruginosa, which indicates that meropenem can pass through the outer membrane via both the D2 channel and another undefined route(s). Antimicrob Agents Chemother. 1993 December; 37(12): 2743-2746

Rice, L B; Marshall, S H; Carias, L L; Sutton, L; Jacoby, G A

doi: 10.1128/AAC.pmid: 8109951

Genes for MGH-1, YOU-1, and YOU-2 extended-spectrum beta-lactamases have been cloned and sequenced. The gene for MGH-1 has the sequence of blaTEM-10, YOU-2 has that of blaTEM-12, and YOU-1 has that of blaTEM-26. All have evolved from blaTEM-1b but have the strong dual promoter sequence of blaTEM-2. Antimicrob Agents Chemother. 1993 December; 37(12): 2760-2761

Maass, G; Immendoerfer, U; Koenig, B; Leser, U; Mueller, B; Goody, R; Pfaff, E

doi: 10.1128/AAC.pmid: 7509144

Thiazolo-iso-indolinone derivatives with high specificity toward the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) were identified. The most potent compound, BM +51.0836, inhibited HIV-1 RT at a 50% inhibitory concentration of 90 nM in vitro. In cell culture assays, similar 50% inhibitory concentrations were obtained with high specificity for HIV-1. These substances were equally active against a zidovudine-resistant isolate. No antiviral effect was observed with an HIV-2 isolate. HIV-1 isolates resistant to the thiazolo-iso-indolinones were generated in cell culture, and the nucleotide sequences of the respective RT genes were analyzed subsequently. Comparison of the deduced amino acid sequences with the wild-type sequence showed an amino acid change at position 181 (Tyr to Cys). Substitutions of amino acid Lys-101 and Lys-103 as well as Tyr-181 and/or Tyr-188 by site-directed mutagenesis led to resistance against the thiazolo-iso-indolinones. A chimeric HIV-2 RT, substituted with amino acids at positions 179 to 190 from HIV-1, acquired only partial susceptibility to BM +51.0836. Antimicrob Agents Chemother. 1993 December; 37(12): 2612-2617

J N Galgiani

doi: N/Apmid: N/A

Johnson, C A; Ateshkadi, A; Zimmerman, S W; Hughes, G S; Craig, W A; Carey, P M; Borin, M T

doi: 10.1128/AAC.pmid: 8109931

Pharmacokinetics of cefpodoxime, an extended-spectrum cephalosporin, were determined for eight noninfected patients on continuous ambulatory peritoneal dialysis (CAPD) and eight healthy volunteers. Subjects were matched for sex, age (+/- 6 years), and body weight (+/- 10 kg, except for one pair) and received a single 200-mg (cefpodoxime equivalents) oral dose of the prodrug cefpodoxime proxetil in an open-label, paired-design fashion. Dialysate (CAPD group only), plasma, and urine samples were collected and assayed for cefpodoxime by a microbiologic method. In addition, mean bactericidal titers of the effluent dialysate against selected bacterial strains often associated with CAPD-related peritonitis were determined at 6 and 24 h after the dose. There was a significant difference (P < 0.05) in all pharmacokinetic parameters between healthy and CAPD subjects, except for lag time to absorption. The mean peak plasma cefpodoxime concentration of 1.88 +/- 0.6 micrograms/ml occurred at 2.44 +/- 0.5 h for healthy volunteers, while the peak concentration of 3.25 +/- 1.4 micrograms/ml occurred at 12.0 +/- 4.2 h for patients on CAPD. The average elimination half-life in CAPD patients was approximately 12 times greater than that seen in healthy volunteers. Peritoneal dialysis had a minimal effect on cefpodoxime clearance. In healthy volunteers, 24.2% +/- 13% of the dose was recovered from the urine, in contrast to only 5.59% +/- 6.9% for CAPD patients. The mean bactericidal titers for all CAPD patients, at 6 and 24 h, were mostly less than 1:2 and did not exceed 1:4 for any of the isolates. Because of the decreased renal clearance and negligible dialysate clearance of cefpodoxime, and delayed drug absorption, the dosage interval for cefpodoxime proxetil may need to be extended in CAPD patients. Antimicrob Agents Chemother. 1993 December; 37(12): 2650-2655

Miyazaki, H M; Kohno, S; Miyazaki, Y; Mitsutake, K; Tomono, K; Kaku, M; Koga, H; Hara, K

doi: 10.1128/AAC.pmid: 8109952

The efficacy of intravenous itraconazole solubilized in hydroxypropyl-beta-cyclodextrin was assessed in a rat model of Aspergillus fumigatus pneumonia. Immunosuppressed rats were infected by intratracheal inoculation of A. fumigatus conidia. Intravenous administration of various doses of itraconazole was started immediately after infection and continued once a day for 7 days. A 10-mg dose of intravenous itraconazole per kg was as effective on survival as 1 mg of amphotericin B per kg daily (a survival rate of 100% in 28 days), while treatment with 1 mg/kg did not increase the survival rate. The 50% lethal dose of intravenous itraconazole given to immunosuppressed and uninfected rats for 7 days was 24.5 mg/kg/day. A microbiological assay to estimate accumulation in tissue after five daily intravenous administrations of itraconazole at 10 mg/kg showed that itraconazole and its active metabolites were present in the lungs for at least 6 h, reaching the MIC as previously described (B. Dupont and E. Drouchet, Rev. Infect. Dis. 9(Suppl. 1):71-76, 1987; A. Espinel-Ingroff, S. Shadomy, and R. J. Gebhart, Antimicrob. Agents Chemother. 26:5-9, 1984). Intravenous itraconazole was considered to be worth evaluating in clinical trials of aspergillosis. Antimicrob Agents Chemother. 1993 December; 37(12): 2762-2765