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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/S0002-9378(97)80008-7 Byline: M. Kolben, J. Blaser, K. Ulm, M. Schmitt, K.T.M. Schneider, H. Tschesche, H. Graeff Keywords: Angiogenin; HELLP syndrome; preeclampsia-eclampsia; Doppler flow; trophoblast invasion Abstract: OBJECTIVE: Our purpose was to determine the levels in plasma of angiogenin in healthy pregnant women and to examine whether there are differences between uncomplicated pregnancies and patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets, preeclampsia-eclampsia, and highly pathologic Doppler flow findings without additional complications. STUDY DESIGN: Angiogenin was measured with a novel enzyme-linked immunosorbent assay. A case control and observational study was conducted in 68 healthy women from the tenth to fortieth weeks of pregnancy and in 18 patients with the syndrome of hemolysis, elevated liver enzymes, and low platelets, 21 with preeclampsia/eclampsia and 13 with highly pathologic Doppler flow findings at admission for delivery. RESULTS: Between the tenth and fortieth weeks of uncomplicated pregnancy angiogenin plasma levels rose from 150 to 250 ng/ml (significant correlation). In patients with highly pathologic Doppler flow findings angiogenin is significantly reduced compared with healthy pregnant matched pairs (150 vs 219 ng/ml, p < 0.01). CONCLUSION: Rising plasma angiogenin levels in pregnancy may reflect persisting placental transformation and remodeling processes; in patients with highly pathologic Doppler flow findings these processes are disturbed and thus placental function is impaired. (Am J Obstet Gynecol 1997;176:37-41.) Author Affiliation: Munich, Germany Article History: Received 29 January 1996; Revised 5 June 1996; Accepted 9 September 1996 Article Note: (footnote) [star] From the Department of Obstetrics and Gynecologya and the Institute for Medical Statistics and Epidemiology,b Technical University of Munich, and the Division of Chemistry, Department of Biochemistry, University of Bielefeld.c , [star][star] Supported by the Deutsche Forschungsgemeinschaft within the framework of the Clinical Research Group GR 280/4-1 (Project Schn 395/3-1-II B 10) at the Department of Obstetrics and Gynecology, Technical University of Munich, and the Sonderforschungsbereich SFB/223 (Project B 1), University of Bielefeld., a Reprint requests: Martin Kolben, MD, Frauenklinik und Poliklinik der Technischen Universitat Munchen, Klinikum rechts der Isar, Ismaninger Str. 22, D-81675 Munchen, Germany., aa 6/1/77899

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’.

Serum kinetics of trimethoprim and sulfamethoxazole were studied in 23 patients during oral and i.v. treatment ofPneumocystis cariniipneumonia. Daily doses of 15–22 mg/kg trimethoprim and 75–110 mg/kg sulfamethoxazole were given every 6 h. Despite administration of a loading dose of twice the regular dose, serum trough concentrations continuously rose from 12 h to 96 h by 63% for trimethoprim and 102% for sulfamethoxazole. After 4–6 days mean trough concentrations of trimethoprim and sulfamethoxazole were 7.7 ± 3.0 and 198 ± 74 mg/l, with individual values of < 4.6 and < 103 mg/l in two patients and > 11.4 and > 307 mg/l in two others. Patients treated orally or i. v. had similar serum levels. However, large interindividual variability was observed despite weight-specific dosing. Administration of a loading dose did not prevent accumulation of serum levels of trimethoprim and sulfamethoxazole over several days of treatment.

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.

Intra- and interindividual variability in the serum kinetics and renal elimination of netilmicin was investigated in a controlled study in 6 healthy, male volunteers. The antibiotic was administered on 2 single days, separated by a 3 week interval. Netilmicin 2 mg/kg lean body mass was given i.m. twice (b.i.d.) and three times (t.i.d.) in a crossover design. 54 blood and 28 urine samples per volunteer were analysed by a radio-enzymatic assay. 24 h serum kinetics were best described by a two compartment open model with time-dependent serum clearance. The latter decreased intraindividually on both study days, from a mean of 82 to 68 ml/min (p<0.05). A similar decrease was observed in the 12 h creatinine clearance. Because drug administration started in the morning, this finding reflects the physiological circadian rhythm in the glomerular filtration rate. The corresponding half-lives of netilmicin rose from 149 to 171 min. Striking intraindividual variation in absorption half-life was observed in all volunteers, ranging from less than 4 to more than 30 min. Comparison of the pharmacokinetic parameters derived from data of the first and second study, revealed a significant intraindividual reduction in the volume of distribution (mean decrease 13%) and in the serum clearance of netilmicin (-8%). Analysis of the serum data of the b.i.d. and t.i.d. dosing schedules showed no difference in the pharmacokinetic parameters; there was significantly higher urinary recovery with the t.i.d. (+9%) than with the b.i.d. schedules. After both days, the 24 h creatinine clearance decreased significantly, by more than 10%. A slight nephrotoxic effect, induced by a therapy for one day with netilmicin, can be deduced from these data.

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 105 or 107 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.

The bactericidal effect of gentarrucin on Pseudomonas aeruginosa ATCC 27853 was investigated in a computer controlled dynamic in-vitro model, which allows the simultaneous simulation of three different dosing regimens for several days. The same total dose reduced cfu-counts of Pseudomonas aeruginosa most effectively, when administered with peak concentrations of 32 mg/l every 32 h, whereas the other dosing regimens with peak concentrations of 16 mg/l every 16 h and 8 mg/l every 8 h were distinctly less effective following the second and subsequent doses. It was shown that the use of a microcomputer facilitates the in-vitro investigation of multiple dosing regimens but counting of cfu cannot be substituted by automatic measurements of turbidity when rapid bactericidal effects occur.

Objective:To examine the role of cytokines in cervical dilation.

Little is known about how many bacteria are present at an infectious focus at the onset of antibiotic therapy. The number of cfu was determined in pus and infected peritoneal fluids obtained from 41 patients. Pathogens were detected in 71% of specimens. There were high concentrations of bacteria in culture-positive samples, in both soft-tissue and peritoneal infections, averaging 2 x 10(8) cfu/mL. These concentrations were much higher than the standard inoculum size used in in-vitro susceptibility tests, 5 x 10(5) cfu/mL. The impact of this discrepancy on antibacterial efficacy was studied with amikacin, ciprofloxacin, imipenem and piperacillin against Escherichia coli and Staphylococcus aureus. The inhibitory and bactericidal activities of amikacin and ciprofloxacin determined with high inocula were two to four times lower than with standard inocula, whereas the activity of piperacillin was diminished at least 128-fold. Similar activity was observed with these drugs in Mueller-Hinton broth and peritoneal fluid. The bactericidal activity of imipenem was reduced in peritoneal fluid. Thus, conditions prevailing at the infection site may compromise antibiotic activity determined in vitro.

During once-daily dosing regimens of aminoglycosides, administration of large single doses results in high peak levels and low 24-h trough levels. However, commercial assays for monitoring aminoglycoside levels are designed to cover the smaller range of serum concentrations usually observed during multiple daily dosing regimens. The study assessed (a) the range of serum concentrations during once-daily dosing of amikacin and (b) the performance of a widely used assay system for measuring concentrations within this range. A total of 42 dosing intervals from eight patients receiving a once-daily regimen of amikacin (20 mg/kg) were monitored. Median (and range) of peak, 8− and 24-h trough levels were 61 (25–89), 5.9 (2.2–19), and 1.3 (<0.8–6.2) mg/L, respectively. The accuracy of a fluorescence polarization immunoassay for measuring concentrations of amikacin during once-daily dosing regimens was assessed in an international multicenter study. The performance of the assay was excellent for peak and 8-h concentrations; median deviations from the target concentrations were <5. The majority of the trough levels (26 of 42) measured in patients during once-daily treatment were within the range of 1–2 mg/L and could also be determined with an accuracy sufficient for clinical monitoring (median deviations 14).

The purpose of this prospective randomized open trial was to investigate the impact of monitoring concentrations in serum on the efficacy and side effects of high-dose co-trimoxazole therapy. Forty consecutive patients with microscopically confirmed Pneumocystis carinii pneumonia were enrolled. Therapy was started with 5 and 25 mg of trimethoprim and sulfamethoxazole, respectively, per kg of body weight given every 6 h for 2 days and continued every 8 h either with (group A) or without (group B) monitoring and dose adjustments according to sulfamethoxazole levels in serum (target, 150 to 200 micrograms/ml) for a total of 21 days. Only 7 of 19 patients (83%). Patients who were treated for the full period and patients for whom co-trimoxazole was prematurely stopped had similar concentrations of sulfamethoxazole (157 +/- 52 versus 155 +/- 47 micrograms/ml) and trimethoprim (5.0 +/- 1.4 versus 5.6 +/- 1.0 microgram/ml). Concentrations of sulfamethoxazole and trimethoprim in group A (158 +/- 39 and 5.6 +/- 1.8 micrograms/ml, respectively) did not differ from those in group B (153 +/- 57 and 5.1 +/- 1.6 micrograms/ml, respectively), and the average daily maintenance doses for groups A (75.4 mg/kg plus 15.1 mg/kg) and B (76.4 mg/kg plus 15.3 mg/kg) were nearly identical. Although the average sulfamethoxazole concentrations were maintained within the target zone in the monitoring group (day 5, 160 +/- 44 micrograms/ml; day 10, 160 +/- 41 micrograms/ml; day 15, 168 +/- micrograms/ml; and day 21, 157 +/- 95 micrograms/ml), only 28% of the individual sulfamethoxazole levels were within the target range of 150 to 200 micrograms/ml after the dose adjustments (32% in group B without intervention). Response rates were similar in both groups. Complete response or improvement was observed in 18 of 19 (group A) and 19 of 21 (group B) patients. The method used for monitoring sulfamethoxazole levels with subsequent dose adjustment did not allow us to reliably achieve the target concentrations and did not significantly alter the incidence of side effects or the efficacy of the therapy.

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.

Results from model tumour systems suggest that either increased levels of certain metalloproteases (MMPs) or decreased levels of their inhibitors correlate with metastatic potential. In this study, levels of two MMPs, i.e. MMP-8 and -9, and their inhibitor tissue inhibitor of metalloprotease type 1 (TIMP-1) were measured by enzyme-linked immunosorbent assay in human breast tumours. Levels of MMP-8 and -9 correlated significantly with each other, but neither MMP correlated with urokinase plasminogen activator. Levels of both MMP-8 and -9 were also significantly related to levels of TIMP-1. In contrast, neither MMP correlated with plasminogen activator inhibitor. No relationship was found between MMP-8, MMP-9 or TIMP-1 and either tumour size or metastasis to axillary nodes. MMP-8 and -9 levels were inversely related to levels of oestrogen receptors. MMP-8 but not MMP-9 levels were also inversely correlated with progesterone receptor levels. It is concluded that the assay for MMP-8 and -9 described here will permit the evaluation of these proteases as prognostic markers in cancer.

Summary 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.

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.

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.

Serum kinetics of amikacin were investigated in 17 severely ill patients. During both the first and last dose intervals of therapy, the serum concentration time course of every patient was documented by 17 blood samples. Six of the patients had moderate to severe renal insufficiency (serum creatinine greater than 1.5 mg/100 ml). In this group of patients, a pronounced rise in serum half-life of amikacin was observed, increasing from a mean of 11.2 to 21.5 h for the first and last interval, respectively. In contrast, mean half-life remained stable in the group of 11 patients with normal renal function. No change in mean serum creatinine occurred in either group, when data from the beginning and the end of therapy were compared. Therefore, the increase of amikacin half-life is apparently not due to a reduction of the glomerular filtration rate, but rather to a decrease of the ratio of amikacin to creatinine clearance. Indeed, a significant reduction of this ratio could be shown in the seven patients in which 24-h creatinine clearance was determined during the first and last day of therapy. This phenomenon is discussed in the context of aminoglycoside accumulation in deep compartments. We conclude that the daily dose of amikacin has to be reduced during therapy in patients with impaired, but stable, renal function.

Since their introduction one or more decades ago, aminoglycosides have generally been administered in multiple daily (i.e. twiceor thrice-daily) dosing regimens. However, nephrotoxicity can be reduced in animal models by administering the same total daily dose as one large dose instead of as multiple small doses. In addition, in vitro and in vivo studies that considered the impact of dosing regimens on efficacy suggest that once-daily dosing is equally or more effective compared to multiple daily dosing. Once-daily versus multiple daily dosing regimens have been compared for amikacin, netilmicin, and gentamicin in 24 randomized, clinical trials including a total of 3,181 patients. An analysis of these studies revealed superior results for once-daily regimens with respect to clinical efficacy (89.5 % vs. 84.7%, p<0.001) as well as bacteriological efficacy (88.6% vs. 83.4%, p<0.01). No statistically significant differences were noted for toxicity. Nevertheless, both nephrotoxicity and ototoxicity occurred less frequently during once-daily dosing (4.5% vs. 5.5% and 4.2% vs. 5.8%, respectively). Finally, once-daily dosing is more economical, since less nursing time and infusion material are required and the efforts for drug monitoring can be reduced. In conclusion, amikacin, netilmicin, and gentamicin can be administered once a day.

Several in vitro and in vivo studies as well as clinical trials have demonstrated that once-daily aminoglycoside regimens are as effective as or more effective than multiple daily dosings. However, the most favorable aminoglycoside dosing regimen for treating enterococcal endocarditis remains controversial. The same total dose of netilmicin was administered as once-daily (24-micrograms/ml peaks) and thrice-daily (8 micrograms/ml) regimens in a pharmacodynamic in vitro model simulating exposure of Enterococcus faecalis to human serum kinetics. Netilmicin was administered in combination with continuous infusions of amoxicillin, vancomycin, or penicillin against a bacterial biofilm adhering to glass beads. No significant differences in bacterial killing were found after 24 or 48 h between the once- and thrice-daily regimens. Additional experiments considering animal kinetics (half-life of netilmicin, 20 min) instead of human kinetics (half-life, 2.5 h) in the pharmacodynamic model also revealed similar results. The addition of netilmicin synergistically increased the activity of vancomycin (P < 0.05). In contrast, amoxicillin alone was as effective as the combination with netilmicin. Thus, it could not be established in this model that once-daily dosing of aminoglycosides is contraindicated for treating infections caused by E. faecalis.

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.

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.

The NMR signals of the nuclei 2H, 35Cl, 37Cl, 79Br and 81Br have been investigated in aqueous solutions. The concentration dependence of the NMR signals of 35Cl and 81Br has been determined in solutions of alkali halides and alkali perchlorates in H2O and D2O and the large solvent isotope effect on the chemical shift has been established. The ratios of the Larmor frequencies of the halide nuclei relative to 2H have been measured with high accuracy. Using the concentration dependence, the ratios of the Larmor frequencies of the halide nuclei for infinite dilution relative to 2H in pure D2O are given. From these ratios, magnetic moments for the halide nuclei have been derived.

A double-blind study was designed to test the hypothesis that local side-effects during i. v. administration of erythromycin lactobionate depend on the drug concentration and that they can therefore be minimized by dissolving erythromycin in a larger infusion volume. Forty healthy students were assigned in a randomized sequence to four 30 min infusions: 120 and 250 ml of erythromycin lactobionate (1 g in 0.9% NaCl) and 120 and 250 ml of placebo (0.9% NaCl). An unexpectedly high incidence (95% and 80% for the infusion volumes of 120 and 250 ml, respectively) of severe systemic side-effects was observed during the first 79 infusions. Because all of these systemic side-effects were associated with the infusion of erythromycin, the study was terminated at this point. Side-effects included abdominal cramps, nausea, vomiting, dizziness and profuse sweating. The postulated positive effect of lower erythromycin concentrations in the infusion on local side-effects (pain at the infusion site, erythema) was marginal (63% vs. 45%). Compared to the systemic side-effects, the problem of local tolerance is less important. In young adults, 30 min infusions of 1 g erythromycin lactobionate are associated with a high incidence of systemic side-effects which may be due to an age-dependent effect of the drug on smooth muscle. Um die Hypothese zu erhärten, daß lokale Nebenwirkungen während i. v. Applikation von Erythromycin-Lactobionat von der Medikamentenkonzentration abhängen und demzufolge durch Auflösen von Erythromycin in einem größeren Infusionsvolumen vermindert werden können, wurde die folgende Doppelblind-Studie konzipiert: Jeder von 40 gesunden Studenten sollte in einer randomisierten Sequenz vier 30-min Infusionen erhalten: 120 ml und 250 ml Erythromycin-Lactobionat (1 g in 0,9% NaCl) und 120 ml und 250 ml Plazebo (0,9% NaCl). Während der ersten 79 Infusionen wurde eine unerwartet hohe Inzidenz von schweren systemischen Nebenwirkungen beobachtet: 95% bei einem Infusionsvolumen von 120 ml und 80% bei einem Infusionsvolumen von 250 ml. Sämtliche systemischen Nebenwirkungen wurden durch die Infusion von Erythromycin-Lactobionat hervorgerufen. Aus diesem Grunde wurde die Studie zu diesem Zeitpunkt abgebrochen. Die Nebenwirkungen umfaßten Bauchkrämpfe, Nausea, Erbrechen, Schwindel und Schweißausbrüche. Der postulierte positive Effekt von niedrigeren Medikamentenkonzentrationen im Infusat auf das Auftreten von lokalen Nebenwirkungen (Schmerzen an der Infusionsstelle, Rötung) war marginal (63% vs. 45%). Verglichen mit den unerwarteten, systemischen Nebenwirkungen ist das Problem der lokalen Toleranz von geringerer Bedeutung. Bei jungen Erwachsenen sind 30-min Infusionen von 1 g Erythromycin-Lactobionat mit einer hohen Inzidenz an systemischen Nebenwirkungen verbunden, welche durch einen altersabhängigen Effekt des Medikamentes auf die glatte Muskulatur bedingt sein könnten.

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.

Ciprofloxacin and enoxacin were two- to fourfold less active against Pseudomonas aeruginosa in calcium- and magnesium-supplemented broth compared with unsupplemented broth regardless of inoculum size, presence of serum, or use of inhibitory or bactericidal endpoints (P less than 0.01). The effect of cation supplementation was less pronounced and less consistent for Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus.

Summary The prevalence of HIV antibodies in various groups at risk was studied in 1,546 persons in Zürich. The prevalence was 17% (39/236) in homosexual men, 7% (13/180) in bisexual men, and 45% (14/31) and 42% (22/53) in female and male intranvenous drug abusers, respectively. Heterosexual transmission appeared to be the route of infection in four seropositive persons (two women and two men) who had no homosexual contacts and were not drug abusers (4/1050).

ATOMIC frequency standards have been in regular operation in several laboratories for the past few years. It has rapidly become clear that they can be used for comparisons with astronomical time determinations.

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.

SEVERAL atomic frequency standards of different types are now in use for comparisons with astronomically determined time. As the adopted frequencies of these atomic standards have been derived from the smoothed universal time U.T.2, which is itself variable in time1, they disagree by several parts in 109. In order to obtain a uniform base for the atomic times determined by the different standards, their frequencies have to be compared directly. This has been done between cæsium resonators at the National Physical Laboratory in Teddington and the Naval Observatory in Washington using the GBR 19.6 kc./s. transmissions. Later the same comparison was repeated between similar cæsium resonators at the National Physical Laboratory2.