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Biomedical subjects

G G Zhanel

Publications and source records attributed to G G Zhanel.

At least 19 recordsLinked to original sources
PubMed1999

Characterization of the inoculum effect with Haemophilus influenzae and beta-lactams.

An inoculum effect is defined as a four-fold or greater increase in MIC with an increase in bacterial inocula. Haemophilus influenzae was tested for an inoculum effect with ampicillin, cefuroxime, and amoxicillin/clavulanate using the standard initial inocula (5 x 10(5) CFU/mL) and a higher initial inocula (1 x 10(7) CFU/mL). An inoculum effect was observed with both beta-lactamase (TEM-1, ROB-1) positive and beta-lactamase negative strains of H. influenzae when MICs were determined based on turbidity. MICs based on viable cell counts however, demonstrated that only beta-lactamase positive strains of H. influenzae produced an inoculum effect. These observations suggest that MICs determined based on turbidity, using high initial inocula, are not reliable when examining the inoculum effect in H. influenzae. The magnitude of the inoculum effect with beta-lactamase positive strains was beta-lactam dependent (ampicillin > amoxicillin/clavulanate > cefuroxime). beta-lactam kill-curves confirmed the aforementioned results. Addition of the beta-lactamase inhibitor clavulanate completely reversed the inoculum effect in beta-lactamase (TEM-1 and ROB-1) positive strains of H. influenzae with all beta-lactams tested. Introduction of the beta-lactamase gene TEM-1 on plasmid vector pLS88 into a beta-lactamase negative strain of H. influenzae (Rd) produced an inoculum effect based on viable cell counts. In conclusion, our results suggest that the beta-lactam inoculum effect demonstrated by H. influenzae is the result of beta-lactamase production and is poorly assessed by turbidity.

Anti-Bacterial Agents↗
PubMed1999

Synergy of an investigational glycopeptide, LY333328, with once-daily gentamicin against vancomycin-resistant Enterococcus faecium in a multiple-dose, in vitro pharmacodynamic model.

The pharmacodynamics of an investigational glycopeptide, LY333328 (LY), alone and in combination with gentamicin, against one vancomycin-susceptible and two vancomycin-resistant Enterococcus faecium strains were studied with a multiple-dose, in vitro pharmacodynamic model (PDM). Dose-range data for the PDM studies were obtained from static time-kill curve studies. In PDM experiments conducted over 48 h, peak LY concentrations of 0.1x and 1x the MIC every 24 h and peak gentamicin concentrations of 18 micrograms/ml every 24 h (Gq24 h) and 6 micrograms/ml every 8 h (Gq8 h) were studied alone and in the four possible LY-gentamicin combinations. Compared to either antibiotic alone, LY-gentamicin combination regimens produced significantly higher apparent killing rates (KRs) calculated during the initial 2 h postdosing. The mean KRs for LY or gentamicin alone versus those for the LY-gentamicin combination regimens were 0.35 +/- 0.55 log10 CFU/ml/h (95% confidence interval [CI95%], 0 to 0.70) and 1.46 +/- 0.71 log10 CFU/ml/h (CI95%, 1.01 to 1.91), respectively (P < 0.0001). Bacterial killing at 48 h (BK48), which was calculated by subtracting the bacterial counts at 48 h from the initial inoculum, with a negative value indicating net growth, was also significantly greater. The mean BK48S were -0.69 +/- 0.44 log10 CFU/ml (CI95%, -0.41 to -0.97) and 3.72 +/- 2.28 log10 CFU/ml (CI95%, 2.28 to 5.17) for LY or gentamicin alone versus LY-gentamicin combination regimens, respectively (P < 0.0001). None of the 12 regimens with LY or gentamicin alone but 75% (9 of 12) of the LY-gentamicin combination regimens were bactericidal. Eighty-three percent (10 of 12) of the LY-gentamicin combination regimens also demonstrated synergy. No significant differences between the pharmacodynamics of LY-gentamicin combination regimens containing Gq24 h versus those containing Gq8h were detected.

Anti-Bacterial Agents↗
PubMed1999

In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients.

Fluconazole-resistant Candida albicans and intrinsically fluconazole-resistant Candida species have been reported as bloodstream isolates. However, an association between the isolation of fluconazole-resistant Candida from the bloodstream and patient risk factors for fungemia has not been established. The purpose of this study was to determine the prevalence of fluconazole resistance in bloodstream isolates of Candida species and Cryptococcus neoformans collected from patients with neutropenia, one of the most important risk factors for fungemia. MICs of voriconazole, fluconazole, itraconazole, ketoconazole, amphotericin B, and flucytosine were determined by the National Committee for Clinical Laboratory Standards M27-A method (1997). Voriconazole, on a per-weight basis, was the most active azole tested. Fluconazole resistance (MIC >/= 64 microg/ml) was not identified in any of the C. albicans (n = 513), Candida parapsilosis (n = 78), Candida tropicalis (n = 62), or C. neoformans (n = 38) isolates tested.

Candida↗
PubMed1998

In vitro activities of six fluoroquinolones against Canadian isolates of vancomycin-sensitive and vancomycin-resistant Enterococcus species.

The in vitro activities of six fluoroquinolones were determined against 1482 Enterococcus species isolates collected as part of a 1996 Canadian surveillance study. Clinafloxacin MIC90s were 4 or 8 microg/mL, trovafloxacin and BAY 12-8039 MIC90s were 8 or 16 microg/mL, sparfloxacin MIC90s were 32 microg/mL, and ciprofloxacin and ofloxacin MIC90s were >32 microg/mL for the vancomycin-sensitive Enterococcus faecalis, vancomycin-sensitive Enterococcus faecium, and vancomycin-resistant E. faecium isolates collected.

Anti-Bacterial Agents↗
PubMed1998

Comparison of CO2 generation (BACTEC) and viable-count methods to determine the postantibiotic effect of antimycobacterial agents against Mycobacterium avium complex.

The postantibiotic effects (PAEs) of antimycobacterial agents determined with a BACTEC TB-460 instrument (CO2 production) and by a traditional viable-count method against Mycobacterium avium complex (MAC) were not significantly different (P > 0.05). The longest PAEs following a 2-h exposure to 2x the MIC were induced by amikacin (10.3 h), rifampin (9.7 h), and rifabutin (9.5 h), while the shortest PAEs resulted from clofazimine (1.7 h) and ethambutol (1.1 h) exposure. CO2 generation is a valid and efficient means of determining in vitro PAEs against MAC.

Amikacin↗
PubMed1998

Influence of human serum on pharmacodynamic properties of an investigational glycopeptide, LY333328, and comparator agents against Staphylococcus aureus.

The MICs and MBCs of 15 antibiotics for two strains of Staphylococcus aureus were determined in Mueller-Hinton broth (MHB) and 90% serum-10% MHB. Subsequent experiments established that highly protein-bound antibiotics (>/=80%), such as LY333328, demonstrated higher MICs and MBCs, less killing over an 8-h interval, and shorter postantibiotic effects in 90% serum-10% MHB than in MHB alone. Albumin was demonstrated to be almost solely responsible for changes in the aforementioned pharmacodynamic parameters of LY333328.

Anti-Bacterial Agents↗
PubMed1998

Susceptibilities of Candida species isolated from the lower gastrointestinal tracts of high-risk patients to the new semisynthetic echinocandin LY303366 and other antifungal agents.

Fifty-two percent of stool specimens collected from 1,200 high-risk patients were colonized with yeasts, primarily Candida albicans (53. 6%) and Candida glabrata (35.7%). Susceptibilities to all antifungal agents tested, including LY303366, were similar to those reported previously for Candida species isolated from blood.

Anidulafungin↗
PubMed1998

Screening of stool samples for identification of vancomycin-resistant Enterococcus isolates should include the methyl-alpha-D-glucopyranoside test to differentiate nonmotile Enterococcus gallinarum from E. faecium.

The methyl-alpha-D-glucopyranoside (MDG) test has been shown to be superior to motility testing in differentiating Enterococcus faecium from E. gallinarum. In the present study, 33 vancomycin-resistant enterococcus (VRE) isolates collected as part of a stool surveillance study were compared by using motility and MDG. Motility testing identified all 33 isolates as E. faecium, whereas MDG identified 11 of the 33 isolates as nonmotile E. gallinarum. The MDG results were confirmed by sequencing the 16S rDNA V6-to-V8 region. We conclude that the MDG test is a necessary component of routine VRE screening.

Anti-Bacterial Agents↗
PubMed1997

In vitro antifungal activity of BMS-181184 against systemic isolates of Candida, Cryptococcus, and Blastomyces species.

BMS-181184 is a water-soluble derivative of the pradimicin group of antifungal compounds. We determined the in vitro activities of BMS-181184 and comparator agents amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 184 systemic fungal isolates collected at the Health Sciences Centre in Winnipeg, Canada, between 1987 and 1995. BMS-181184 demonstrated MICs of between 1 and 8 micrograms/mL for all Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, Candida lusitaniae, and Cryptococcus neoformans isolates tested. BMS-181184 was less active against Candida parapsilosis (MIC90 = 16 micrograms/mL) and Blastomyces dermatitidis (MIC90 = 32 micrograms/mL). Isolates of Candida species with fluconazole MICs of > or = 16 micrograms/mL and those with fluconazole MICs of < or = 8 micrograms/mL demonstrated similar BMS-181184 sensitivities.

Anthracyclines↗
PubMed1997

Candidemia in a Canadian tertiary care hospital from 1976 to 1996.

The incidence of candidemia was reviewed at the Health Sciences Centre in Winnipeg, Canada, over a 21-year period (1976 to 1996). Candida species were identified as blood-stream isolates in significantly (p < 0.05) higher numbers from 1991 to 1996 than in the previous 15 years. Antifungal susceptibilities remained unchanged with Candida albicans isolates tested from 1985 to 1996. Retrospective chart reviews revealed that all patients with candidemia possessed at least two risk factors. The main risk factors identified were recent or concurrent antibiotic therapy (95% of patients), presence of a central line (93% of patients), and immunosuppression (88% of patients). Treatment generally involved amphotericin B therapy (81% of patients), and death occurred in 52% of the patients. Mortality directly attributable to Candida species could be established in 23% of patients.

Adolescent↗
PubMed1997

Altered denA and anr gene expression in aminoglycoside adaptive resistance in Pseudomonas aeruginosa.

Adaptive resistance to aminoglycoside killing and cytoplasmic accumulation occurs in cultures of originally susceptible Pseudomonas aeruginosa following an initial incubation with aminoglycoside. Anaerobiosis has also been reported to reduce bacterial killing and limit cytoplasmic aminoglycoside accumulation. We hypothesized that a common mechanism may facilitate reduced bacterial killing and aminoglycoside accumulation in both cases. Northern blot analysis of P. aeruginosa adaptively resistant to gentamicin demonstrated increased mRNA levels of both denA (nitrite reductase), which facilitates terminal electron acceptance in the anaerobic respiratory pathway, and its regulatory protein, ANR, in the absence of promoter DNA sequence changes, when compared with controls. These observations suggested that P. aeruginosa may regulate the expression of genes in its anaerobic respiratory pathway in response to aminoglycosides and may explain, at least partially, P. aeruginosa adaptive resistance to aminoglycosides.

Aminoglycosides↗
PubMed1997

In vitro kill curves of a new semisynthetic echinocandin, LY-303366, against fluconazole-sensitive and -resistant Candida species.

In vitro killing by a new semisynthetic echinocandin, LY-303366, was characterized using clinical isolates of fluconazole-sensitive (Y58) and -resistant (Y180) Candida albicans as well as Candida glabrata (Y7) and Candida krusei (Y171). The 24-h kill curves for Y58 and Y180 demonstrated dose-independent killing of between 1 and 2 log10 with LY-303366 at concentrations of 0.1, 1, 10, 50, 100, and 1,000 times the MIC. Regrowth did not occur at 24 h with either C. albicans isolate at the aforementioned LY-303366 concentrations. At their MICs, LY-303366 and amphotericin B produced similar killing kinetics in cultures of Y58, Y180, Y7, and Y171, while all cultures exposed to fluconazole at its MIC demonstrated stasis or growth over 24 h.

Anidulafungin↗
PubMed1997

In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species.

The in vitro activities of LY-303366, a new semisynthetic echinocandin, and comparators amphotericin B, 5-fluorocytosine, fluconazole, and ketoconazole against 205 systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species were determined. LY-303366 had MICs of < or = 0.32 microg/ml for all Candida albicans (n = 99), Candida glabrata (n = 18), and Candida tropicalis (n = 10) isolates tested. LY-303366 was also active against Aspergillus species (minimum effective concentration at which 90% of the isolates are inhibited, 0.02 microg/ml) (n = 20), was less active against Candida parapsilosis (MIC at which 90% of the isolates are inhibited [MIC90], 5.12 microg/ml) (n = 10), and was inactive against C. neoformans (MIC90, >10.24 microg/ml) (n = 15) and B. dermatitidis (MIC90, 16 microg/ml) (n = 29).

Anidulafungin↗
PubMed1996

Antibiotic activity in microbiological media versus that in human urine: comparison of ampicillin, ciprofloxacin, and trimethoprim-sulfamethoxazole.

The activities of three antibiotics in both Mueller-Hinton broth (MHB) and pooled human urine were compared by using an in vitro pharmacodynamic model. Clinical and reference strains of Escherichia coli were exposed to antibiotics at concentrations achievable in human urine. The rate of bacterial killing (time to a reduction of 3 log10 CFU/ml) and the extent of bacterial killing at 24 h were examined. Between MHB and urine, there were no significant differences in the rate or extent of bacterial killing for both ampicillin and ciprofloxacin. For trimethoprim-sulfamethoxazole there was no significant difference in the extent of bacterial killing in urine compared with that in MHB (P > 0.1); however, there was a significant decrease in the rate of bacterial killing in urine compared with that in MHB (P < 0.001). We conclude that with ampicillin and ciprofloxacin, activity against E. coli in MHB is predictive of the effects in human urine. The activity of trimethoprim-sulfamethoxazole in MHB predicts the extent but not the rate of bacterial killing in human urine.

Ampicillin↗
PubMed1996

In vitro characterization of aminoglycoside adaptive resistance in Pseudomonas aeruginosa.

Aminoglycoside adaptive resistance was characterized in one reference strain and four clinical isolates of Pseudomonas aeruginosa. Adaptive resistance was initiated with a 2-h gentamicin or tobramycin exposure at the MIC. Each P. aeruginosa strain demonstrated an adaptive-resistance period of between 8 and 12 h when tested with both aminoglycosides. Aminoglycoside adaptive resistance was shown to correlate with a decrease in [3H] gentamicin accumulation and a small (5%) but significant (P < 0.05) reduction in proton motive force. The mean generation time of P. aeruginosa during peak levels of adaptive resistance (i.e., maximum reductions in aminoglycoside killing) was not significantly different from that of control organisms (P < 0.05). No changes in outer membrane protein or lipopolysaccharide sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles were noted when control, adaptively resistant, and postadaptively resistant cells were compared. Cytoplasmic membrane profiles of adaptively resistant cells, however, demonstrated several band changes when compared with control and postadaptively resistant cells. We conclude that the decrease in aminoglycoside accumulation associated with adaptive resistance in P. aeruginosa may be, in part, a function of reductions in proton motive force and/or cytoplasmic membrane protein changes. However, the importance of these changes requires further investigation.

Anti-Bacterial Agents↗
PubMed1996

Vancomycin-resistant enterococci.

OBJECTIVE: To review vancomycin resistance in enterococci (Enterococcus faecalis and Enterococcus faecium) with respect to history, epidemiology, mechanism of resistance, and management. DATA SOURCES: A MEDLINE, IDIS, and current journal search of English-language articles on vancomycin-resistant enterococci (VRE) published between 1982 and 1994 was conducted. STUDY SELECTION: Studies and reports pertaining to vancomycin-resistant E. faecalis and E. faecium were evaluated. Case reports, cohort, epidemiologic, in vitro and in vivo studies were evaluated. DATA EXTRACTION: Reports in which vancomycin minimum inhibitory concentrations were 32 micrograms/mL or more were evaluated. DATA SYNTHESIS: Large outbreaks of VRE infection have occurred as a result of nosocomial spread. Such outbreaks have required intensive infection control procedures to limit the spread of VRE. Vancomycin resistance in E. faecalis and E. faecium has been subdivided into phenotypes, VanA and VanB. The mechanism of vancomycin resistance is caused by the production of depsipeptide D-Ala-D-Lac, which replaces D-Ala-D-Ala in the peptidoglycan pathway, thereby preventing the binding of vancomycin to D-Ala-D-Ala in the peptidoglycan cell wall. The vanA gene is associated with a transpositional element (Tn1546) that can be transferred via conjugation while most data suggest that vanB has an endogenous origin. Education, aggressive infection control practices. surveillance programs, and appropriate use of vancomycin are necessary to respond to the VRE problem. CONCLUSIONS: The prevalence of VRE has increased significantly in recent years and has become a worldwide problem. Several factors, such as prior exposure to vancomycin and antibotics (e.g., cephalosporins, antianaerobic agents), physical location in the hospital, immunosuppression, prolonged hospital stay, and VRE gastrointestinal colonization are associated with VRE infection and colonization. Antibiotic treatment of serious VRE infection depends on the phenotype. Optimal treatment of the VanA phenotype is unknown; the VanB phenotype may be treated with teicoplanin and an aminoglycoside.

Animals↗
PubMed1995

Prevalence of asymptomatic bacteriuria and associated host factors in women with diabetes mellitus. The Manitoba Diabetic Urinary Infection Study Group.

A prospective study was undertaken to determine the prevalence of significant asymptomatic bacteriuria in adult women with diabetes mellitus attending endocrinology clinics at two tertiary-care university-affiliated teaching hospitals. In addition, host factors of the patients were correlated with bacteriuria. The overall prevalence of bacteriuria was 7.9% (85 cases per 1,072 women). Absolute urinary leukocyte (white blood cell) counts were > or = 10/mm3 in 77.6% (66) of the 85 bacteriuric women vs. 23.7% (234) of the 987 nonbacteriuric women (P < .001). Bacteriuric women were significantly more likely than nonbacteriuric women to have non-insulin-dependent diabetes mellitus, longer duration of diabetes, neuropathy, and heart disease. Aboriginals had bacteriuria at a significantly higher prevalence rate than that among nonaboriginals (19.7% [15 of 76] vs. 7.0% [70 of 996], respectively; P < .0001), were more likely to have occult upper urinary tract infection (antibody-coated bacteria positivity: 53% [8 of 15] vs. 20% [10 of 50], respectively; P = .016), and had significantly lower urinary leukocyte counts, whether they were bacteriuric or not (P < .05). Multivariate analysis identified duration of diabetes and aboriginal origin as independent risk factors for the presence of bacteriuria.

Adolescent↗