Jürg Blaser

Comparative study with enoxacin and netilmicin in a pharmacodynamic model to determine importance of ratio of antibiotic peak concentration to MIC for bactericidal activity and emergence of resistance.

An in vitro pharmacokinetic model was used to study the comparative antibacterial activities of multiple-dose regimens of enoxacin and netilmicin. Strains of Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Staphylococcus aureus were exposed to changing drug concentrations, mimicking human two-compartment pharmacokinetics. Oral administration was simulated for the quinolone, and intravenous administration was simulated for the aminoglycoside. Similar ratios of peak concentration to MIC resulted in similar changes in bacterial concentrations over time with both compounds. Following the initial dose, a rapid bactericidal effect occurred, with a greater than 99% reduction of the bacterial counts within 4 h at peak concentrations more than three times the MIC. However, bacterial regrowth occurred within 24 h unless the peak concentration/MIC ratio exceeded 8:1 (P less than 0.01). For the regrowing bacteria, MICs were four- to eightfold higher, and little or no bactericidal effect occurred following the second and subsequent doses. These data demonstrate the equally potent bactericidal activity of orally administered enoxacin and intravenously administered netilmicin. Selection of resistant subpopulations was similar with each drug. The peak concentration/MIC ratio may be an important parameter in the clinical use of quinolone and aminoglycoside antibiotics.

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.

Efficacy of intermittent versus continuous administration of netilmicin in a two-compartment in vitro model.

Several aminoglycoside dosage regimens were studied in a kinetic in vitro model. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus were exposed in serially placed artificial capillary units to netilmicin concentrations that changed based on human two-compartment pharmacokinetics. The same total dose per 24 h was administered as a continuous infusion (3.7 micrograms/ml) or in 1-h infusions given every 24 (24 micrograms/ml) or 8 h (8 micrograms/ml). The once daily administration showed the best response in terms of either faster killing of E. coli, K. pneumoniae, and S. aureus or greater reduction of the inocula of P. aeruginosa. After 28 h of treatment, however, all regimens reduced the nonpseudomonads by more than 99.99%, whereas all three P. aeruginosa strains regrew to greater than 10(8) CFU/ml due to selection of resistant subpopulations. In contrast to the bactericidal effect of the first dose, no killing occurred after subsequent doses if the ratio of peak drug concentration to MIC was low (less than or equal to 6). These results support the concept of administering high doses of aminoglycosides once every 24 h.

Analysis of pH, pO2 and pCO2 in drainage fluid allows for rapid detection of infectious complications during the follow-up period after abdominal surgery

Low pH (<7.1) and pO2 (<6.5 kPa) and high pCO2 (>8 kPa) of peritoneal fluid have been previously associated with the presence of intra-abdominal infection. These parameters were monitored in drainage fluid following emergency laparotomy in 40 patients operated on for intra-abdominal infections and also in 15 patients who underwent laparotomy for another reason than infection. Significant differences were observed beginning on the fourth postoperative day between the 48 patients who improved or were cured and the seven patients in whom therapy failed due to anastomotic breakdown or abscess formation. Anastomotic leaks or abscesses were radiologically confirmed. In five of the seven failures, complications were first detected by analysis of pH, pO2 and pCO2 before clinical symptoms became evident. Specificity for each of these parameters in drainage fluid samples obtained after the second postoperative day was >94%. Assessment of the three parameters allowed for simple, cost-effective, rapid and early detection of infectious complications following abdominal surgery. Tiefe Werte für pH (<7,1) und pO2 (<6,5 kPa) sowie hohe Werte für pCO2 (>8 kPa) in Peritonealflüssigkeit haben sich als charakteristische Parameter einer bakteriellen Infektion erwiesen. Diese drei Parameter wurden in Drainageflüssigkeiten gemessen, die von 40 Patienten nach notfallmäßiger Laparotomie infolge intraabdominaler Infektion gesammelt wurden. Zum Vergleich wurden auch Drainageflüssigkeiten von 15 Patienten asserviert, die aus anderen Gründen laparotomiert wurden. Vom vierten postoperativen Tag an wurden signifikante Differenzen festgestellt zwischen der Gruppe der 48 Patienten, die geheilt oder gebessert und der Gruppe jener sieben Patienten, deren Therapie wegen Anastomosenleck oder Abszeßbildung als Mißerfolg gewertet wurde. Anastomosenlecks and Abszeßbildungen wurden jeweils radiologisch bestätigt. Bei fünf der sieben Patienten, deren Therapie als Mißerfolg klassifiziert wurde, konnte die Komplikation auf Grund der Analyse von pH, pO2 und pCO2 in Drainagesekreten vermutet werden, bevor klinische Symptome manifest wurden. Die Spezifität aller drei Parameter, die in Drainageflüssigkeiten nach dem zweiten postoperativen Tag gemessen wurden, lag über 94%. Die Messung der drei Parameter erlaubt eine einfache, rasche, kostengünstige und frühe Erkennung infektiöser Komplikationen nach Laparotomien.SummaryLow pH (<7.1) and pO2 (<6.5 kPa) and high pCO2 (>8 kPa) of peritoneal fluid have been previously associated with the presence of intra-abdominal infection. These parameters were monitored in drainage fluid following emergency laparotomy in 40 patients operated on for intra-abdominal infections and also in 15 patients who underwent laparotomy for another reason than infection. Significant differences were observed beginning on the fourth postoperative day between the 48 patients who improved or were cured and the seven patients in whom therapy failed due to anastomotic breakdown or abscess formation. Anastomotic leaks or abscesses were radiologically confirmed. In five of the seven failures, complications were first detected by analysis of pH, pO2 and pCO2 before clinical symptoms became evident. Specificity for each of these parameters in drainage fluid samples obtained after the second postoperative day was >94%. Assessment of the three parameters allowed for simple, cost-effective, rapid and early detection of infectious complications following abdominal surgery.ZusammenfassungTiefe Werte für pH (<7,1) und pO2 (<6,5 kPa) sowie hohe Werte für pCO2 (>8 kPa) in Peritonealflüssigkeit haben sich als charakteristische Parameter einer bakteriellen Infektion erwiesen. Diese drei Parameter wurden in Drainageflüssigkeiten gemessen, die von 40 Patienten nach notfallmäßiger Laparotomie infolge intraabdominaler Infektion gesammelt wurden. Zum Vergleich wurden auch Drainageflüssigkeiten von 15 Patienten asserviert, die aus anderen Gründen laparotomiert wurden. Vom vierten postoperativen Tag an wurden signifikante Differenzen festgestellt zwischen der Gruppe der 48 Patienten, die geheilt oder gebessert und der Gruppe jener sieben Patienten, deren Therapie wegen Anastomosenleck oder Abszeßbildung als Mißerfolg gewertet wurde. Anastomosenlecks and Abszeßbildungen wurden jeweils radiologisch bestätigt. Bei fünf der sieben Patienten, deren Therapie als Mißerfolg klassifiziert wurde, konnte die Komplikation auf Grund der Analyse von pH, pO2 und pCO2 in Drainagesekreten vermutet werden, bevor klinische Symptome manifest wurden. Die Spezifität aller drei Parameter, die in Drainageflüssigkeiten nach dem zweiten postoperativen Tag gemessen wurden, lag über 94%. Die Messung der drei Parameter erlaubt eine einfache, rasche, kostengünstige und frühe Erkennung infektiöser Komplikationen nach Laparotomien.

Factors compromising antibiotic activity against biofilms of Staphylococcus epidermidis.

Abstract Several factors associated with bacterial biofilms were studied for their role in phenotypic resistance to antibiotics. These factors included bacterial slime extracted from biofilms, reduced growth rates of biofilm-embedded bacteria and high bacterial inocula. Antibiotic activity against suspended bacteria in the presence of these factors, either alone or combined, was compared with activity against adherent biofilms. All MICs, determined by standard susceptibility tests, were below the sensitivity breakpoints for Staphylococcus epidermidis strain V2. The addition of bacterial slime to suspended bacteria reduced the bactericidal activity of glycopeptides but had less or no effect on the activity of the other antibiotics tested. High bacterial inocula affected the activity of flucloxacillin and quinolones only moderately or not at all, though a more pronounced effect on glycopeptides was observed. In contrast, the bactericidal activity of most antibiotics was severely compromised when adherent bacterial biofilms were used as inocula. In conclusion, the presence of slime, slow growth rates and high bacterial counts may explain the poor activity of glycopeptides against biofilm-embedded organisms, but these factors, either alone or in combination, do not explain the lack of bactericidal activity of other drugs against biofilms. Thus, additional factors need to be identified.

Comparative Multiple-Dose Pharmacokinetics of Cefotaxime, Moxalactam, and Ceftazidime

The pharmacokinetics of cefotaxime, moxalactam, and ceftazidime were investigated in six human volunteers who received in a crossover fashion doses of 0.5, 1.0, and 2.0 g of each drug by a 5-min infusion. Doses of 1.0 g were repeated after the administration of probenecid. Serum and urine concentrations were assayed with an agar diffusion method. Serum concentrations of moxalactam exceeded those of ceftazidime at all times and were distinctly higher than those of cefotaxime. The normalized area under the concentration time curve (defined as the ratio of the area under the curve per dose) reflects this relationship: compared with cefotaxime the normalized area under the curve of moxalactam was 3 to 4 times higher, and that of ceftazidime was 2 to 3 times higher. By intra-individual comparisons, the area under the curve of moxalactam was 44% larger than that of ceftazidime. With increasing doses, cefotaxime exhibited a nonlinear increase of the area under the curve. The half-lives of moxalactam, ceftazidime, and cefotaxime were 2.34, 1.95, and 1.16 h, respectively. The volume of distribution averaged 0.20 ± 0.03, 0.23 ± 0.02, and 0.25 ± 0.04 liters per kg, and the mean total body clearance was 84, 131, and 328 ml/min for moxalactam, ceftazidime, and cefotaxime, respectively. The 24-h urinary recovery was highest for moxalactam (75 ± 4%) followed by ceftazidime (68 ± 11%) and cefotaxime (53 ± 6%). The influence of probenecid on serum concentrations, half-life, area under the curve, and clearance was most apparent with cefotaxime, whereas the pharmacokinetics of moxalactam and ceftazidime were only slightly affected. After the 0.5− and 2.0− g doses of cefotaxime, desacetyl-cefotaxime activity (determined by high-pressure liquid chromatography) reached a peak of 2.7 and 9.9 μg/ml and declined with a half-life of 1.9 and 1.4 h. The ratio of the R(−) and S(−) epimers of moxalactam, which could be differentiated by high-pressure liquid chromatography, fell rapidly from 0.81 at 0.17 h to 0.5 at 5 h, indicating the presence of twice as much of the microbiologically less active S(−) epimer. From a pharmacokinetic standpoint it appears reasonable to conclude that moxalactam and possibly ceftazidime could be administered twice daily and that cefotaxime could be administered three or even four times daily.

Human Pharmacology of Cefotaxime (HR 756), a New Cephalosporin

Cefotaxime (HR 756) is a new semisynthetic parenteral cephalosporin with exceptional activity against gram-negative organisms and considerable stability against their β-lactamases. To study its pharmacokinetic properties, 0.5-, 1-, and 2-g doses were administered to each of six volunteers intravenously over 15 min, followed by a sustaining infusions of 0.5, 1, and 2 g/h, respectively, for 3 consecutive hours. The loading doses produced mean peak levels of 41, 93, and 160 μg/ml, and mean steady-state serum concentrations were 27, 64, and 138 μg/ml, respectively. The mean terminal half-life was 75 ± 7 min. The total volume of distribution averaged 0.22 ± 0.03 liters/kg of body weight. Total body and renal clearances were 232 ± 30 and 145 ± 24 ml/min per 1.73 m2, respectively; 63 ± 9% of the administered dose was excreted through the kidneys in 24 h. To determine the effect of cefotaxime on the renal tubules, urinary alanine aminopeptidase excretion was measured before, during, and after the infusions. It remained within the normal range in all instances; however, 48 ± 14% of the total daily alanine aminopeptidase output was recovered during the infusion period. Side effects were dose related and included fatigue, loose stools, and night sweats. No significant changes in hematology, serum chemistry, or urinalysis were recorded.

Physician compliance with advanced electronic alerts for preventing venous thromboembolism among hospitalized medical patients

Summary.  Background: Worldwide, more than half of the hospitalized medical patients at high risk do not receive venous thromboembolism (VTE) prophylaxis. Although VTE among hospitalized patients at risk is reduced with electronic alerts (eAlerts), the majority of eAlerts are being ignored by the responsible physician. Methods: We investigated physician compliance with an advanced eAlert system in 1027 (age 59 ± 17 years) hospitalized medical patients. A continuously flashing non‐interruptive eAlert, visible to all healthcare professionals, was issued in the electronic patient chart 6 h after admission if the physician did not order prophylaxis. Results: The rate of appropriate prophylaxis increased from 44% before to 76% after the implementation of the eAlert system. Although the patients whose physicians cared for ≥ 20 patients during the study period had a more frequent physician response to the eAlert than patients whose physicians cared for fewer patients (69% vs. 40%, P < 0.001), they received appropriate prophylaxis less often (72% vs. 81%, P = 0.016). After adjustment for significant patient predictors of appropriate prophylaxis, including cancer, age, duration of hospital stay, and thrombocytopenia, patients whose physicians cared for ≥ 20 patients during the study period were less likely to receive appropriate prophylaxis (odds ratio 0.65, 95% confidence interval 0.44–0.96; P = 0.032) than patients whose physicians cared for fewer patients. Conclusions: The introduction of an advanced eAlert system accompanied by continuing medical education for the prevention of VTE resulted in a substantial increase in the rate of appropriate prophylaxis among hospitalized medical patients. However, many eAlerts may cause decreased physician compliance owing to ‘alert fatigue’.

Autosterilization of biodegradable implants by injection molding process

Sterilization of degradable implants by standard procedures may damage the parts due to the labile chemical nature of the polymers. This study examined whether the injection molding process used for the production of polymeric parts may itself sterilize the implant due to high temperature, pressure, and shear forces applied. Poly-D,L-lactic acid (PDLLA) and poly-L-lactic acid (PLLA) granules were contaminated with thermoresistant spores of Bacillus stearothermophilus (>10(5) spores/g). Sterile and contaminated granules of both polymers were injection molded and tested for sterility. All 27 samples produced with sterile PDLLA and processed at 120 degrees C and all 18 samples produced with sterile PLLA at 200 degrees C remained sterile after injection molding and handling. However, in five out of 28 PDLLA samples and in one out of 26 PLLA samples produced with contaminated material, spores had survived the process. In conclusion, the injection molding process could not reliably sterilize parts produced with polylactic acid granules that were heavily contaminated with thermoresistant organisms. However, the number of viable spores was significantly reduced by more than 99.99%. Thus, the injection molding process might allow the autosterilization of parts produced with raw material that is not heavily contaminated.

Impact of netilmicin regimens on the activities of ceftazidime-netilmicin combinations against Pseudomonas aeruginosa in an in vitro pharmacokinetic model.

The antibacterial activities of ceftazidime and netilmicin were studied in a two-compartment in vitro model. Pseudomonas aeruginosa cultures were exposed to changing drug concentrations that mimic human pharmacokinetics. Netilmicin alone reduced the numbers of organisms in cultures of the susceptible strains by more than 99% within 4 h; however, regrowth occurred after 8 h. Although ceftazidime alone killed more slowly than netilmicin, only one of the five strains regrew within 28 h. When both drugs were combined, rapid initial killing occurred without subsequent regrowth. Studied after 24 h in combination with ceftazidime, netilmicin was as effective when given as a single daily dose as when administered in three daily doses that provided 50% more aminoglycoside per day. Decreased bacterial susceptibility was seen after ceftazidime exposure for one strain and after netilmicin exposure for all originally netilmicin-susceptible strains. No such reduction in susceptibility was observed during exposure to the combination. The results of standard in vitro checkerboard tests for synergism were predictive of the initial (4 to 8 h) but not the final (24 to 28 h) assessment of drug interaction in the pharmacokinetic model.