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J Blaser

Publications and source records attributed to J Blaser.

At least 37 records · Page 2Linked to original sources
PubMed1995

In vivo verification of in vitro model of antibiotic treatment of device-related infection.

Device-related infections are difficult to treat with antibiotics alone. Standard susceptibility tests do not correlate with treatment success. Therefore, the utility of a pharmacokinetic in vitro model has been evaluated in comparison with the tissue-cage infection model in guinea pigs. The bactericidal activity of 28 treatment regimens has been studied by using three different test strains. In vitro efficacy was defined as reduction in the number of suspended or adherent bacteria, and in vivo efficacy was defined as reduction in the number of bacteria in tissue-cage fluid. Test results between the two models (in vivo and in vitro) correlated well, with correlation coefficients of 0.85 for in vivo efficacy versus in vitro efficacy against suspended bacteria and 0.72 for in vivo efficacy versus in vitro efficacy against adherent bacteria (P < 0.05) for Staphylococcus aureus, 0.96 and 0.82 (P < 0.05) for Staphylococcus epidermidis, and 0.89 and 0.97 for Escherichia coli, respectively. In contrast, standard susceptibility tests, ratios of MICs to trough or peak levels, ratios of the area under the curve to the MIC, or time above the MIC were not predictive for therapeutic outcome in either the in vitro or in vivo model. In both models, the bactericidal activity levels with combination regimens were significantly higher than those with single-drug regimens (P < 0.001). Furthermore, rifampin combinations with either vancomycin, teicoplanin, fleroxacin, or ciprofloxacin were significantly more bactericidal against adherent bacteria than netilmicin combinations with vancomycin or daptomycin (P < 0.01). Thus, in vivo verification of the pharmacokinetic in vitro model correlated well with the animal model. The in vitro model offers an alternative to ther animal model in experiments that screen and assess antibiotic regimens against device-related infections.

Animals↗
PubMed1995

Biochemical analysis of peritoneal fluid in patients with and without bacterial infection.

OBJECTIVE: To find out if the concentrations of biochemical variables in peritoneal fluid differed in the presence or absence of infection. DESIGN: Prospective study. SETTING: University hospital, Switzerland. SUBJECTS: 80 patients undergoing abdominal operations, 23 of whom were operated on for an intra-abdominal infection. 57 Patients with no sign of infection served as controls. MAIN OUTCOME MEASURES: Concentrations of 24 biochemical variables measured in specimens of peritoneal fluid obtained during the operation. RESULTS: Major differences between specimens taken from infected and uninfected patients including: glucose 5.4 compared with 0.8 mmol/l, lactate 7.9 and 17.2 mmol/l, aspartate aminotransferase 83 and 520 U/l, phosphate 1.1 and 3.7 mmol/l, potassium 4.5 and 10.1 mmol/l, lactate dehydrogenase 2021 and 7998 U/l, and gamma-glutamyl transferase 57 and 169 U/l. CONCLUSION: Intra-abdominal infection significantly alters the composition of peritoneal fluid. The assessment of milieu factors at the site of infection may help in the design of more predictive in vitro tests to guide antimicrobial treatment of intra-abdominal infections. In addition, the knowledge of discriminatory variables in peritoneal fluid may be useful in the diagnosis of intra-abdominal infection.

Abdomen↗
PubMed1994

Role of amoxicillin serum levels for successful prophylaxis of experimental endocarditis due to tolerant streptococci.

The importance of amoxicillin serum profiles for successful prophylaxis of experimental endocarditis in rats was assessed. Animals with catheter-induced vegetations were challenged intravenously with large inocula of Streptococcus sanguis and received one of the following amoxicillin dosages: single or multiple bolus injection of 40 mg/kg; 40 mg/kg administered as a continuous infusion over 12 h; or either 9 or 18 mg/kg administered over 12 or 24 h, respectively. The regimen producing a single transient high peak serum level failed to prevent experimental endocarditis; in contrast, a second injection 6 h after the first resulted in successful prophylaxis. Likewise, the three regimens of continuous, relatively low-dose regimens prevented infections. Thus, the most important parameter for successful prophylaxis was the duration of inhibitory concentration of the drug in the serum. The total dose of antibiotic, the peak serum levels, or the area-under-the-curve values were not predictive of successful prophylaxis.

Amoxicillin↗
PubMed1994

Monitoring serum concentrations for once-daily netilmicin dosing regimens.

A once-daily dosing regimen for aminoglycosides is less expensive, at least as effective and possibly less toxic than multiple-daily dosing regimens. Once-daily dosing might also allow the frequency of measuring the serum concentrations of these antibiotics to be reduced since two of the major objectives of monitoring, high peak and low trough concentrations, are more likely to be achieved with this regimen. A novel strategy for monitoring serum concentrations which relies on a single sample obtained 8 h after a dose, as opposed to both trough and peak samples, is evaluated here. Serum kinetics of netilmicin were studied prospectively in 51 adult patients with initial serum creatinine concentrations of < 130 mumol/L who were treated with a median daily dosage of 400 mg. Concentrations measured 8 h after administration were within the target range of 1.5-6 mg/L in 113 of 134 dosing intervals studied. Concentrations above and below this range correlated significantly with higher and lower 24-h trough concentrations and areas under the curve respectively. There was also a significant correlation between 8-h netilmicin concentrations and nephrotoxicity (P < 0.05); a relative increase of > or = 25% in the serum creatinine concentration or an absolute increase of > 25 mumol/L was detected in 0 of 7 patients with an 8-h concentration of < 1.5 mg/L, in 3 of 33 patients (9.1%) with an 8-h concentration of 1.5-6 mg/L and in 4 of 11 patients (36%) with an 8-h concentration of > 6 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats.

The pharmacokinetic determinants of successful antibiotic prophylaxis of endocarditis are not precisely known. Differences in half-lives of antibiotics between animals and humans preclude extrapolation of animal results to human situations. To overcome this limitation, we have mimicked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering the drug through a computerized pump. Rats with catheter-induced vegetations were challenged with either of two strains of antibiotic-tolerant viridans group streptococci. Antibiotics were given either through the pump (to simulate the whole kinetic profile during prophylaxis in humans) or as an intravenous bolus which imitated only the peak level of amoxicillin (18 mg/liter) in human serum. Prophylaxis by intravenous bolus was inoculum dependent and afforded a limited protection only in rats challenged with the minimum inoculum size infecting > or = 90% of untreated controls. In contrast, simulation of kinetics in humans significantly protected animals challenged with 10 to 100 times the inoculum of either of the test organisms infecting > or = 90% of untreated controls. Thus, simulation of the profiles of amoxicillin prophylaxis in human serum was more efficacious than mere imitation of the transient peak level in rats. This confirms previous studies suggesting that the duration for which the serum amoxicillin level remained detectable (not only the magnitude of the peak) was an important parameter in successful prophylaxis of endocarditis. The results also suggest that single-dose prophylaxis with 3 g of amoxicillin in humans might be more effective than predicted by conventional animal models in which only peak levels of antibiotic in human serum were stimulated.

Amoxicillin↗
PubMed1993

Effect of pathological changes of pH, pO2 and pCO2 on the activity of antimicrobial agents in vitro.

Since standard susceptibility tests reflect the physiological rather than the pathological conditions prevailing within an infected abdomen, as recently documented, the effect of reduced pH and pO2 and increased pCO2 on the activity of antibiotics in vitro was studied. MICs were determined in vitro under standard culture conditions (MICstandard) and modified conditions (MICmodification) simulating the previously determined pathological values. Various classes of antibiotics were affected differently by the modified conditions. However, within an antibiotic class similar results were obtained for gram-negative and gram-positive pathogens. Median MICmodification/MICstandard ratios were 4 for aminoglycosides, 2 for quinolones and clindamycin, 1 for cephalosporins, and 0.5 for penicillins and vancomycin. Anaerobic conditions and a pH of 6.4 further increased the ratio of aminoglycosides to 8. Ratios were similar within an antibiotic class at inocula of 10(5) or 10(7) cfu/ml. All MICs determined in tests with imipenem against gram-negative and gram-positive bacteria and with vancomycin against gram-positive organisms were below the susceptibility breakpoint, whatever conditions and inocula were employed. In contrast, the percentage of MICs in susceptibility range using high inocula and modified conditions decreased to 78% for penicillins, 73% for cephalosporins, 22% for aminoglycosides, 11% for quinolones and 0% for clindamycin. In conclusion, routine susceptibility testing may overestimate the activity of aminoglycosides and underestimate the activity of beta-lactams under the conditions prevailing during abdominal infection.

Abdomen↗
PubMed1993

Analysis of pH and pO2 in abscesses, peritoneal fluid, and drainage fluid in the presence or absence of bacterial infection during and after abdominal surgery.

The diagnostic significance of pH, pO2 (partial pressure of oxygen), and pCO2 (partial pressure of carbon dioxide) was studied in pus, peritoneal fluid, and drainage fluid obtained during or after abdominal surgery. Measurements of these fluids in 59 patients with clinically and bacteriologically documented abdominal or anorectal infection (median pH: 6.75, median pO2: 28 mm Hg, median pCO2: 89 mm Hg) differed significantly (p < 0.001) from data of 105 patients undergoing elective laparotomy for a reason other than infection (median pH: 7.49, median pO2: 144 mm Hg, median pCO2: 92 mm Hg). The combined use of a threshold criterion for pH and pO2 allowed for excellent discrimination between infected (pH less than 7.1, pO2 less than 49 mm Hg) and noninfected patients, with positive and negative predictive values of 98% and 99%, respectively. In conclusion, conditions prevailing during standard in vitro susceptibility tests more closely reflect physiologic conditions as opposed to the conditions prevailing at the site of abdominal infections. Measurements of pH and pO2 allow for an easy, quick, sensitive, and specific diagnosis of bacterial abdominal infection.

Abdomen↗
PubMed1992

Amikacin, ceftazidime, and flucloxacillin against suspended and adherent Pseudomonas aeruginosa and Staphylococcus epidermidis in an in vitro model of infection.

Bacterial inocula were exposed as suspended cultures or as adherent biofilms on glass beads in a novel in vitro model of infection to oscillating drug concentrations mimicking human serum kinetics during clinical treatment. Amikacin was given once or thrice daily alone or in combination with ceftazidime or flucloxacillin against Pseudomonas aeruginosa or Staphylococcus epidermidis. Killing of adherent bacteria was significantly reduced during single-drug treatment compared with suspended bacteria (P less than .001), and beta-lactams were more active than amikacin against both suspended and adherent bacteria (P less than .01). Amikacin-beta-lactam combinations killed the inocula more rapidly and were consistently bactericidal against both suspended and adherent pathogens (P less than .05). Once-daily dosing of amikacin produced greater initial killing than thrice daily dosing (P less than .05), but both regimens were similarly effective after 48 h. The differences in antibiotic activity against suspended and adherent bacteria may relate to clinical failures in the treatment of foreign-body infections by bacteria sensitive to the administered antibiotics, as determined by standard susceptibility tests.

Amikacin↗
PubMed1992

[Follow-up of abdominal surgery by analysis of pH, p02 and pCO2 in drainage fluid].

Milieu factors such as pH, pO2, and pCO2 have previously been shown to permit reliable intraoperative discrimination of infected and non-infected peritoneal or drainage fluid. The presence of infection was associated with pH less than 7.1, pO2 less than 6.5 kPa and pCO2 greater than 8 kPa. These variables were monitored in the immediate postoperative period to quantify clinical improvement and to evaluate their potential for the early detection of infective complications. 21 patients underwent laparotomy for intraabdominal infections such as perforated appendicitis or perforated sigmoid diverticulitis. 5 were operated on for reasons other than infection. Fluid was sampled from a drainage tube every second day for a mean period of 7 days for determination of pH, pO2, and pCO2. A score ranging from 0 (normal) to 6 (severely ill) was calculated from these measurements. Specimens were obtained intraoperatively from 14 patients with documented infections and their mean score averaged 5 (range 3-6). Specimens were obtained on days 4 and 6 from 18 patients whose progress was uneventful and their mean score was 0.3 (range 0-2). 4 of these 26 patients developed postoperative infections after anastomotic breakdown, and each of their scores increased 1-2 days before the infection became clinically obvious, reaching values ranging from 3-6. In contrast, only 1 of 18 patients who made uneventful progress scored greater than 2 after day 3 (p less than 0.01). We conclude that assessment of milieu factors in peritoneal or drainage fluid permits quick and easy monitoring of the postoperative course.

Abdomen, Acute↗
PubMed1991

Combination therapy with ciprofloxacin plus azlocillin against Pseudomonas aeruginosa: effect of simultaneous versus staggered administration in an in vitro model of infection.

The effect of dose scheduling on the pharmacodynamics of simulated human doses of ciprofloxacin (200 mg intravenously [iv] every 12 h) and azlocillin (4 g iv every 12 h) alone or in combination against Pseudomonas aeruginosa was studied in a two-compartment in vitro kinetic model of infection. Studies with the two drugs in combination were compared using simultaneous or staggered (first doses of each drug were administered 6 h apart) dosing schedules. Bacterial regrowth and resistance were prevented by all combination dosing schedules; however, the simultaneous regimen consistently provided the greatest extent of killing for all strains, particularly in those initially resistant to ciprofloxacin. These enhanced effects of the combination were corroborated by an increase in the peak and duration of bactericidal activity in the analogous "serum" compartment of the model. These data show the potential usefulness of simultaneous dosing of an antipseudomonal beta-lactam with ciprofloxacin against P. aeruginosa.

Azlocillin↗
PubMed1991

Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection.

The bactericidal efficacy of amikacin, isepamicin and netilmicin was studied against Pseudomonas aeruginosa and Serratia marcescens over a treatment period of 30 h using two one-compartment in-vitro models with differently designed culture compartments. High bacterial inocula were exposed to fluctuating drug concentrations, simulating human serum concentrations (t1/2 = 2 h) during clinical treatment. The same daily dose was administered as 1 h infusions given every 8 h or every 24 h, resulting in peak concentrations of 8 and 24 mg/l for netilmicin, and 24 and 72 mg/l for amikacin and isepamicin, respectively. Once-daily dosing was more bactericidal during initial treatment in the in-vitro models (P less than 0.01) and at least as effective as thrice-daily dosing in preventing bacterial regrowth, despite a prolonged period of subinhibitory drug concentration before administration of the second dose. Lower ratios of peak concentration to MIC were needed to achieve bactericidal activity (greater than 99.9% reduction of cfu) after 24 h treatment against S. marcescens compared with P. aeruginosa (P less than 0.01). All nine regimens providing peaks of at least four times the MIC were bactericidal against S. marcescens after 24 h exposure. In contrast, a bactericidal effect against P. aeruginosa occurred only during two of six experiments with peaks of four to nine times the MIC. Similar results were obtained in both in-vitro models of infection. These data suggest insufficient intrinsic activity of the aminoglycosides studied for single drug treatment of P. aeruginosa in the absence of host-defence mechanisms.

Amikacin↗
PubMed1991

Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients.

Ten patients with symptomatic HIV infection (six with ARC, four with AIDS) received tetanus and 23-valent pneumococcal vaccination. Anti-tetanus IgG and IgM, and anti-pneumococcal IgG against all 23 capsular types of the vaccine were measured on days 0, 11, 17, 30, and 90. Anti-pneumococcal IgG were simultaneously determined in two plasma pools of 100 healthy unimmunized blood donors and of 112 healthy adults who had previously received a 14-valent pneumococcal vaccination. Peak IgG responses to both vaccines were observed on day 17; thereafter, the antibody levels gradually fell again. Anti-tetanus IgG rose from 0.6 U/ml (geometric mean) to 2.0 U/ml on day 17. Anti-tetanus IgM remained unchanged. Anti-pneumococcal IgG increased only by 1.14-fold compared with pre-vaccination levels (geometric mean of IgG rises against all 23 polysaccharides in 10 patients), and exceeded the upper 95% limit of unvaccinated blood donors in only 30 out of 230 specimens. Pre-vaccination levels for pneumococcal type-specific IgG were significantly higher in HIV-infected patients compared with the pool of unimmunized healthy controls, possibly indicating a higher rate of previous pneumococcal infections in HIV-seropositive subjects. However, post-pneumococcal vaccination levels were significantly lower in HIV-infected patients than in the pool of healthy controls. The increase in anti-tetanus IgG significantly correlated with the level of CD4 lymphocytes and with in vitro lymphocyte proliferation by pokeweed mitogen (5 micrograms/ml) and phytohaemagglutinin (2.5 micrograms/ml), confirming a particularly low vaccination response in patients who were severely immunocompromised.

AIDS-Related Complex↗
PubMed1991

Interface-area-to-volume ratio of interstitial fluid in humans determined by pharmacokinetic analysis of netilmicin in small and large skin blisters.

Human pharmacokinetics of netilmicin during multiple dosing were studied in serum and in the fluid of skin blisters with two different ratios of interface area to fluid volume. The kinetics in the blisters followed the serum concentration-time curve with a delay but with a similar elimination half-life of 2.4 h. The kinetics in the 40-microliters blisters followed closely the theoretically calculated concentrations of the peripheral compartment of a two-compartment model. In contrast, the concentrations in the 120-microliter blisters increased less rapidly, lower peaks were achieved, and concentrations decreased with a significantly longer delay. A very similar area-specific flow or clearance rate of 1.6 microliters.h-1.mm-2 was calculated for the interface area between the serum compartment and either the small or large blisters. The observed rapid mass transfer between serum and blister fluid suggests similar oscillations of concentrations in serum and in small interstitial fluid compartments.

Adult↗
PubMed1990

Novel resistance to imipenem associated with an altered PBP-4 in a Pseudomonas aeruginosa clinical isolate.

A Pseudomonas aeruginosa (isolate 416) from a patient with pneumonia, was initially susceptible to imipenem (MIC: 2 mg/l) but became resistant to this antibiotic (isolate 470, MIC: 32 mg/l) during imipenem therapy. Treatment failed. No parallel increases in MIC were observed for other antimicrobials tested. Isolates 416 and 470 shared the same pyocin type and serotype, produced small amounts of an inducible beta-lactamase, and had similar lipopolysaccharide compositions. On electrophoresis of outer membrane proteins, the porin F, identified by the monoclonal antibody MA4-4, was expressed similarly by the two isolates but the production of one band (apparent molecular weight: 47,000) was diminished in isolate 470. [14C]-Imipenem labelling of intact cells proceeded more slowly in 470 than in 416, especially when bacterial cells were treated by antibody MA4-4 to block the porin F channel. [14C]-Imipenem labelling of penicillin binding proteins (PBP) showed that the band identified as PBP-4 bound markedly less radioactivity in isolate 470 than in 416. After isolate 470 was passaged several times in antibiotic-free broth, the imipenem MIC was decreased from 32 to 8 mg/l, and the [14C]-imipenem PBP pattern recovered the initial profile as exhibited by isolate 416. Two resistance mechanisms, affecting imipenem electively, could have combined their effect in the post-therapy isolate, altered target protein and reduced permeability.

Animals↗
PubMed1990

Enhancement of leucocyte killing of resistant bacteria selected during exposure to aminoglycosides or quinolones.

In vitro exposure to aminoglycosides and quinolones may select resistant subpopulations, although this is not a common clinical problem. This study was designed to determine whether aminoglycoside and quinolone resistant bacteria are more susceptible to leucocyte (WBC) killing. Cultures of Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus were pretreated with aminoglycosides (netilmicin, amikacin) and quinolones (enoxacin, ciprofloxacin) at 1/2 MIC for 24 h. The median susceptibility of bacteria selected during antibiotic exposure was reduced four-fold. These resistant subpopulations (10(6) cfu/ml) were exposed to 10(7) human WBC/ml for 6 h in antibiotic free cell culture media with 10% fresh human serum. Enhanced WBC activity was observed against all antibiotic pretreated bacteria in comparison with untreated controls (P less than 0.01). After 4 h of exposure to WBC, aminoglycoside or quinolone pretreated cultures of P. aeruginosa were reduced by 1.3-1.7 log, in comparison with a reduction of only 0.5 log in control cultures. These observations may explain in part the infrequent therapeutic failure with these drugs in hosts with competent neutrophils despite the potential of these drugs to select resistant strains in vitro.

4-Quinolones↗
PubMed1990

Significance of "extravascular" protein binding for antimicrobial pharmacodynamics in an in vitro capillary model of infection.

The effect of protein binding in an "extravascular" space on antimicrobial pharmacodynamics was studied in an in vitro capillary model of infection. Simulated 500-mg oral doses of dicloxacillin (approximately 96% bound) or cephalexin (less than 5% bound) were administered every 6 h for four doses. A 10-fold-higher dose of dicloxacillin was also studied to determine the effect of drug concentration on the reduction of bacterial killing in the presence of protein. Staphylococcus aureus ATCC 25923 was inoculated into peripheral chambers filled with either Mueller-Hinton broth or Mueller-Hinton broth plus 25% human serum. Serial samples for bacterial counts were collected over 24 h. The presence of serum in the chambers significantly reduced bacterial killing by dicloxacillin but not by cephalexin during the first 6 h (two-way analysis of variance, F = 6.04, P less than 0.05) but not at 24 h. Reduction of dicloxacillin activity in serum-containing chambers persisted with the higher dose. These data suggest that despite attaining higher total drug concentrations in protein-containing extravascular spaces with highly bound drugs, protein binding reduces bactericidal activity during the early stages of treatment in this model.

Anti-Infective Agents↗
PubMed1990

Interactions of antimicrobial combinations in vitro: the relativity of synergism.

Interactions of combinations of netilmicin, amikacin, piperacillin, imipenem, azlocillin, ceftazidime or moxalactam were studied in vitro against Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus. Microtiter checkerboard technique was compared with standard killing curve method and with killing curves obtained in kinetic in vitro models mimicking single or multiple dosing regimens according to human pharmacokinetics. Antibiotic combinations were classified as antagonistic, indifferent or synergistic. Disagreement between classification by checkerboard and by kinetic model was found in 14 of 33 combinations studied (42%). Further analysis by standard killing curve method demonstrated that synergism or antagonism is a relative, not an absolute feature of drug combinations against given pathogens. Factors contributing to disagreements included the concentrations studied relative to the bacterial sensitivity, the ratio of concentrations of the two drugs tested, the size of the bacterial inoculum and the endpoint of the interaction assessment. Standard in vitro methods do not consider changes of antibiotic concentrations over time during combination therapy. Concentrations studied are defined according to bacterial sensitivity (fractions of MIC). Therefore, they may or may not relate to those at the infected site. The observed discrepancies between standard methods for testing drug interaction and a model which more closely reflects human pharmacokinetics support the argument that standard synergy testing provides incomplete data to reliably design clinical combination therapy.

Amikacin↗