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J A Karlowsky

Publications and source records attributed to J A Karlowsky.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1995

Development of multiple-antibiotic-resistant (Mar) mutants of Pseudomonas aeruginosa after serial exposure to fluoroquinolones.

Laboratory-derived fluoroquinolone-resistant mutants were created by serially passaging wild-type Pseudomonas aeruginosa on fluoroquinolone-containing agar to obtain high-level fluoroquinolone resistance (e.g., ciprofloxacin MIC of 1,024 micrograms/ml). With increases of 4- to 32-fold in MICs of fluoroquinolones, these organisms demonstrated (relative to wild-type) normal morphology, resistance to fluoroquinolones only, no change in fluoroquinolone uptake, and no change in lipopolysaccharide profiles or outer membrane protein profiles. Complementation with wild-type Escherichia coli gyrA restored fluoroquinolone susceptibility, suggesting that these were gyrA mutants. After 4- to 32-fold increases in fluoroquinolone MICs (with continued passage on fluoroquinolone-containing agar) isolates demonstrated altered morphology, a multiple-antibiotic-resistant (Mar) phenotype (including cross-resistance to beta-lactams, chloramphenicol, and tetracycline), reduced fluoroquinolone uptake and altered outer membrane proteins (reductions in the 25- and 38-kDa bands as well as several bands in the 43- to 66-kDa region). Complementation with wild-type E. coli gyrA partially reduced the level of fluoroquinolone resistance by approximately 8- to 32-fold, suggesting that these mutants displayed both gyrA and non-gyrA mutations.

Anti-Infective Agents↗
PubMed1994

Postantibiotic effect in Pseudomonas aeruginosa following single and multiple aminoglycoside exposures in vitro.

The effect of single and multiple 2-h aminoglycoside exposures on the duration of the postantibiotic effect (PAE) and bacterial killing were investigated using a reference strain (ATCC 27853) and four clinical isolates of Pseudomonas aeruginosa. Concentration-dependent PAE and bacterial killing were demonstrated following single exposures to amikacin, gentamicin or tobramycin. Cultures were also repeatedly exposed to peak aminoglycoside concentration simulating traditional (three times a day) and once daily dosing regimens. Aminoglycoside re-exposures every 8 h at the original culture MIC produced significant, successive reductions in PAE (P < 0.05) and bacterial killing (P < 0.01) coincident with increases in culture MICs. Identical experiments re-exposing cultures to their predetermined, induced MICs demonstrated similar to significantly longer PAEs (P < 0.05) than those observed following first exposure. Multiple gentamicin or tobramycin exposures at 8 mg/L (traditional peak) every 8 h or 24 mg/L (once daily peak) once every 24 h both showed significant reductions in PAE (P < 0.05) and bacterial killing (P < 0.05) on repeated dosing. However, the once-daily high peak concentration exposure demonstrated significantly longer PAEs and greater bacterial killing both initially and upon re-exposure compared with the 8-hourly exposure. In addition, the once daily dosing regimen maintained substantially larger aminoglycoside concentration/MIC ratios. We conclude that multiple exposure of P. aeruginosa in-vitro, to aminoglycosides at the intervals tested, reduces the PAE and bacterial killing and increases the MICs.

Aminoglycosides↗
PubMed1994

The accumulation of fluoroquinolones in Staphylococcus aureus during the postantibiotic effect.

The accumulation of radiolabelled pefloxacin, norfloxacin, and lomefloxacin was determined in Staphylococcus aureus during log phase growth, the postantibiotic effect (PAE), and at 1, 4 and 6 h post PAE. Uptake in actively growing cells was consistent with a non-saturable passive diffusion process. The addition of metabolic inhibitors significantly increased accumulation consistent with the presence of an energy dependent efflux system. Accumulation of all three fluoroquinolones in PAE phase cells was significantly increased compared to that which occurred in actively growing cells. In contrast to cells in the log phase, addition of metabolic inhibitors to PAE phase cells did not result in a significant increase in drug accumulation. Uptake kinetics 1 h and 4 h post PAE were similar to those found during the PAE phase. Organisms required 6 h after the end of the PAE phase before normal uptake kinetics of fluoroquinolones resumed.

Anti-Infective Agents↗
PubMed1994

Once-daily aminoglycoside dosing assessed by MIC reversion time with Pseudomonas aeruginosa.

A novel, in vitro, pharmacodynamic comparison of single and divided daily dosing regimens of aminoglycosides is described. Experiments were conducted to evaluate the impact of gentamicin and tobramycin concentration on the time required for the MICs for five Pseudomonas aeruginosa strains to revert to their original values (MIC reversion time [MRT]) following single and multiple 2-h aminoglycoside exposures to 8 and 24 mg/liter. Single 2-h aminoglycoside exposures to 8 mg/liter produced culture MRTs (gentamicin, 21.5 +/- 4.0 h; tobramycin, 22.3 +/- 2.8 h) that were significantly (P < 0.05) shorter than those measured following identical exposures to 24 mg/liter (gentamicin, 28.9 +/- 3.8 h; tobramycin, 26.8 +/- 3.1 h). However, three sequential 2-h exposures to 8 mg/liter, one exposure every 8 h, produced MRTs following the third exposure (gentamicin, 68.1 +/- 5.2 h; tobramycin, 77.8 +/- 7.8 h) that were significantly longer (P < 0.005) than those determined following three 2-h exposures to 24 mg/liter, one exposure every 24 h (gentamicin, 36.1 +/- 3.0 h; tobramycin, 34.5 +/- 3.0 h). In addition, the once-daily exposure regimen to 24 mg/liter consistently produced cultures with significantly (P < 0.005) higher aminoglycoside concentration/MIC ratios compared with those for cultures reexposed to 8 mg/liter once every 8 h. These data support the concept of once-daily aminoglycoside dosing.

Anti-Bacterial Agents↗
PubMed1993

In vitro postantibiotic effects following multiple exposures of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli in pooled human cerebrospinal fluid and Mueller-Hinton broth.

Multiple exposures with cefotaxime in either Mueller-Hinton broth or cerebrospinal fluid had no effect on killing or the duration of postantibiotic effect (PAE) in Escherichia coli strains tested. However, upon multiple exposures in Mueller-Hinton broth, ciprofloxacin and gentamicin PAEs significantly decreased with a concomitant reduction in bacterial killing. A reduction in bacterial killing following multiple ciprofloxacin and gentamicin exposures was also seen with cerebrospinal fluid; however, the PAE was maintained.

Cefotaxime↗
PubMed1992

Concepts on the use of liposomal antimicrobial agents: applications for aminoglycosides.

Liposomes are microscopic lipid vesicles consisting of one or more concentric phospholipid bilayers enclosing discrete aqueous spaces. Liposomes provide an apparently nontoxic biological delivery system for hydrophobic and hydrophilic drugs. With few exceptions liposomal antimicrobial drugs are administered intravenously, although other routes have been investigated. Intravenously administered, conventionally prepared vesicles are rapidly cleared from the blood principally by phagocytic cells of the mononuclear phagocyte system (MPS), in particular by macrophages located in the liver (Kupffer's cells) and spleen. The expectation that liposomes would provide a new form of drug carrier capable of diverse physiological selectivity has not been realized. The low endocytotic capacity of many cell types and the inability of liposomes to transverse continuous vascular endothelia have prevented the active targeting of non-MPS tissues with liposomes. Despite their well-documented toxicity and the development of new antimicrobial classes, aminoglycosides continue to have an important antimicrobial role. The encapsulation of aminoglycosides into liposomes may reduce the toxicity associated with the multiple daily administration often required for patients with normal renal function. In addition, the encapsulation of aminoglycosides alters their pharmacokinetics, increases t1/2 and area under the curve, decreases Vd and Cpmax, and causes a shift in drug accumulation from the kidney to other organs, thus potentially reducing nephrotoxicity. Studies demonstrate improved outcome for intracellular infections treated with liposomal aminoglycosides vs. free aminoglycosides. Unresolved questions include what role liposomal aminoglycosides have in the treatment of extracellular infection and whether their sustained release action will promote resistance.

Aminoglycosides↗
PubMed1992

Effect of pooled human cerebrospinal fluid on the postantibiotic effects of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli.

The killing and postantibiotic effects (PAE) of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli were determined in Mueller-Hinton broth (MHB) and pooled human cerebrospinal fluid (CSF). MICs performed in MHB and CSF were within one dilution for all antimicrobial agent-organism combinations. At two times the MIC, CSF significantly (P less than 0.05) increased the duration of the PAE compared with MHB when cefotaxime, ciprofloxacin, and gentamicin were used against all strains tested. This effect occurred despite similar reductions in bacterial growth in both fluids after the 2-h antimicrobial agent exposure. We conclude that pooled human CSF markedly increases the PAE of cefotaxime, ciprofloxacin, and gentamicin against E. coli compared with MHB, without affecting bacterial killing.

Cefotaxime↗
PubMed1991

Antimicrobial activity of subinhibitory concentrations of aminoglycosides against Pseudomonas aeruginosa as determined by the killing-curve method and the postantibiotic effect.

This investigation used the postantibiotic effect (PAE) and killing curves to provide data on the antimicrobial activity of subinhibitory (1/8x, 1/4x and 1/2x minimum inhibitory concentration; MIC) and inhibitory (1x MIC) concentrations of amikacin, gentamicin and tobramycin against Pseudomonas aeruginosa. Subinhibitory concentrations (1/4x and 1/2x MIC) of aminoglycosides demonstrated a reproducible PAE. At 1/4x MIC, the order of duration of the PAE was approximately 15 min for all aminoglycosides, while at 1/2x MIC all three aminoglycosides displayed a similar PAE of approximately 40 min. Killing-curve studies demonstrated that subinhibitory concentrations of aminoglycosides either decrease bacterial growth for several hours (1/4x and 1/2x MIC) or produce stasis of growth for several hours (1/8x MIC). Only inhibitory aminoglycoside concentrations (1x MIC) proved to be bactericidal. Subinhibitory concentrations of aminoglycosides decrease bacterial growth and produce a PAE against P. aeruginosa.

Amikacin↗
PubMed1991

Influence of human urine on the in vitro activity and postantibiotic effect of ciprofloxacin against Escherichia coli.

The purpose of this investigation was to study the effects of human urine on the minimum inhibitory concentration (MIC) and the postantibiotic effect (PAE) of ciprofloxacin against Escherichia coli. MICs and the PAE were performed in Mueller-Hinton broth (MHB; pH 7.3 and 5.5) and in human urine (pH 5.5 and 7.3). In urine, pH 5.5, MICs increased 64-fold (from 0.016 to 1.024 micrograms/ml) and the PAE was abolished (from 101.6 to 3.7 min), when compared to MHB, pH 7.3. An acidic pH demonstrated the greatest effect on reduced susceptibility and PAE. Using ciprofloxacin concentrations adjusted for a higher MIC obtained in pH-adjusted urine and MHB, PAE values were similar for urine and MHB (approximately 280 min at 40 x MIC). This study demonstrated that the MIC and PAE of ciprofloxacin against E. coli are influenced by human urine and in particular its pH.

Ciprofloxacin↗