Pharmacokinetics of methioprim in human volunteers.
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Biomedical subjects
Publications and source records attributed to T Bergan.
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Heat-labile enterotoxin producing strains of Escherichia coli were isolated from diarrheal faeces of humans and from the jejunum of pigs which had died of diarrhea. The heat-labile enterotoxin was assayed by three different enzyme-linked immunosorbent assays (ELISA). The first assay was based upon immunological cross-reactions between the heat-labile enterotoxins of E coli and Vibrio cholerae, the second on specific E coli heat-labile enterotoxin antibodies and the third on affinity of the toxin to the presumed cell membrane receptor, the ganglioside GM1. The heat-labile enterotoxins of human and porcine origin bound equally well to the same extent in the ELISA procedure, which utilized immunological cross-reactivity between the heat-labile enterotoxins of E coli and V cholerae. The reactivity, however, was quite different in the GM1-ELISA. The binding affinity was high between GM1 and enterotoxin produced by E coli strains of human origin, whereas the binding affinity was low for enterotoxin from porcine strains.
Anaerobic bacteria constitute a substantial component of the normal vaginal flora and of the outer cervical canal. Consequently, one would expect infections emanating from the vaginal flora to be caused to a substantial degree by anaerobic bacteria. The anaerobes may contribute in colpitis, but their role is difficult to prove in this situation, since sampling only yields normal flora components. One clue that anaerobes may contribute to colpitis is the circumstance that the flora under those conditions differ from the normal situations. Another is the circumstance that metronidazole, which only inhibits anaerobes, does reduce symptoms e.g. of colpitis in the presence of the microaerophilic Gardnerella vaginalis, which is resistant to metronidazole (but sensitive to the metabolite hydroxymetronidazole). In the US, pelvic inflammatory disease (PID) is to a substantial degree apparently caused by anaerobic bacteria. Our experience in Scandinavia indicates that anaerobes are of neglible importance in this condition, since we rarely isolate anaerobes in spite of adequate sampling, transport and processing of specimens. We mostly find anaerobes in post-operative PID when the vaginal wall has been passed, or as a complication of pregnancy (puerperal fever, early rupture of membranes, abortion), and in connection with intrauterine devices. The role of anaerobes in bartholinitis is established. PID may be associated with appendicitis or colonic diverticulosis. Anaerobes are regularly isolated from abscesses developing in the pelvic organs. This also applies to tuboovarial and vulvovaginal abscesses. The most important anaerobic bacteria in infections of the female genital organs are Bacteroides fragilis and other species of the fragilis group, B. melaninogenicus and related species, other Bacteroides, peptococci and peptostreptococci. Clostridium perfringens rarely cause infections of female genital organs, although such conditions have a dramatic course.
Anaerobic bacteria are particularly frequent in infections following surgery and other trauma implanting bacteria of the normal mucosal flora. A few clinical clues of anerobic infections like smelling pus or discharge, preceeding aminoglycoside therapy or lack of anaerobic bacterial growth are important clues that anaerobes may be involved. Successful recovery of anaerobic bacteria, however, requires special techniques carried out by the clinician. Samples must be taken with a few basic rules in mind: (1) puncturing by syringe is the preferable method of sampling, (3) oxygen must not gain access to the samples (and must be removed before transport to the laboratory, if inadvertently admitted), (4) rapid transport to the laboratory improves the chance of successful recovery of anaerobes, and (5) special transport methods are required for specimens containing anaerobic bacteria.
Quantitative transformation of Acinetobacter calcoaceticus BD4-Ss exposed to autologous DNA in a liquid system was examined with streptomycin resistance as a marker. The exposure to DNA was terminated by addition of DNase at set intervals. The variables tested were concentrations of autologous Sr-DNA, exposure time, growth phase, recipient cell density, and the pH of the liquid transformation system. The ratio of transformants to total number of recipient cells (T/R-ratio) was proportional to the DNA concentration up to a level of about 10 micrograms/ml. There was a constant increase of transformant numbers upon time of exposure. The T/R ratio was highest at the early growth phase, but the total number of transformed cells per ml culture aliquot was only raised by a factor approximately 10 from the earlier to the later growth phases and non increase was observed in recipients grown for more than 3 hours. There was a marked relationship between the relative number of transformants per total number of recipients in that the T/R-ratio was markedly higher with fewer cells per ml in the transformation broth system where exposure to DNA occurred. The transformation was higher at a pH of 7.3 than 7.0. The results enabled definition of the optimal test system for quantitative transformation of A. calcoaceticus with the strain BD4 as recipient.
Quantitative transformation of streptomycin resistance marker was carried out with strains of Acinetobacter calcoaceticus. Standard recipient strain was the competent BD4-Ss. Transformation proceeded in a liquid system with a concentration of 20 micrograms/ml of streptomycin resistant DNA (Sr-DNA) from BD4, 17 reference strains of Acinetobacter, and 42 recent clinical isolates of the acid forming variant (anitratus) and 12 of the non-acid forming variant (lwoffi) as donors of Sr-DNA. The exposure time was 20 min before interruption with DNase and quantitated plating. Among the strains examined were differentiated 16 biotypes as based on oxidative acid production from glucose and lactose, haemolysis, urease, gelatinase, and growth with citrate as the sole carbon source. Autologous transformation gave a transformation of 2.94 (+/- 0.66)% of the recipient cells (quantitated by colony forming units). Sr-DNA from 50 of 63 strains were able to transform BD4-Ss. The transformation ratio was 0.06-6.4% of autologous BD4 transformation. Two further recent clinical isolates were weakly transformation competent. Competence was only found in autologous transformation. The major portion (50/63) of the strains belong to the BD4 genotype of A. calcoaceticus, but the taxonomic position of the 13 non-donors in respect to BD4 could not be evaluated by transformation because of lack of a competent recipient. The strains transforming BD4 belonged to both the glucose acidifyers and the non-acidifyers without genetic distinction. The results are consistent with recognition of both as belonging to the same species, but with their recognition as species variants: A calcoaceticus var, anitratum and A. calcoaceticus var. lwoffi.
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The general pharmacokinetics of first order open one- and two-compartment models are given. Particular attention is drawn to the penetration of peripheral foci by antibiotics. The amount of a substance transported to a focus of infection is proportional to the area under the plasma concentration curve. The peak in peripheral foci appears somewhat later than in the plasma and is a little lower. However, when substances are excreted rapidly from the body the level in peripheral foci often remains above the serum level towards the end of the dosage interval. Intermittent administration achieves a higher peripheral concentration than a continuous infusion of the same dosage.
A heat-labile enterotoxin prepared from E. coli (EcLT) increased fluid secretion and cAMP production by segments of rat ileum in vivo and in vitro. The effect of this toxin was compared to that of cholera toxin (VcLT). The increase of cAMP occurred more rapidly after EcLT than after VcLT indicating a difference in the kinetics of uptake or action of the two toxins. Chlorpromazine (CPZ) 5 mg/kg given by intramuscular injection 1 h before application of the toxins inhibited the increase in cAMP levels and the increase in fluid secretion in vivo. CPZ 10(-4) M given together with the toxins to intestinal loops in vitro inhibited the increase in cAMP levels and fluid secretion by this preparation. Scanning electron microscopy revealed that CPZ caused extensive shedding of the fluid-producing mucosal cells.
The pharmacokinetics of bacmecillinam and pivmecillinam were studied in healthy fasting volunteers given tablets in a cross-over, randomized order. The mean (+/- SD) peak levels of plasma mecillinam were 1.43 +/- 0.34, 2.73 +/- 0.43, and 4.62 +/- 1.41 mg/l after bacmecillinam 100, 200, and 400 mg and 2.38 +/- 0.65 mg/l after pivmecillinam 400 mg. The corresponding areas under plasma Vs time curves (AUC) were 2.21 +/- 0.19, 3.99 +/- 0.63, and 7.74 +/- 1.38 mg . h. l-1 for bacmecillinam and 5.35 +/- 0.93 mg . h. l-1 for pivmecillinam. The elimination half-lives were 0.8-1.1 h for bacmecillinam and 0.7 h for pivmecillinam. The 12 h urinary recovery of unchanged mecillinam after the 400 mg doses was 41% for bacmecillinam and 30% for pivmecillinam. The 400 mg dose of bacmecillinam gave a significantly higher plasma peak (p less than 0.001), AUC (p less than 0.001) and urinary recovery (p less than 0.001) than did pivmecillinam 400 mg. The plasma peaks appeared earlier and the rate of absorption was higher after bacmecillinam than after pivmecillinam (p less than 0.05). In conclusion, bacmecillinam had a better bioavailability than pivmecillinam in the tablet formulations studied. The AUC increased linearly with increasing doses of bacmecillinam.
The pharmacokinetics of netilmicin were analyzed in 30 children, including 13 premature and seven gestationally mature newborns. Ten were children ranging in age from 3.5 months to 13 years. The newborns exhibited more variation in serum levels than the older children, and the premature babies more than those born at term. The serum half-life (t1/2), tended to show higher values in premature than in mature newborns, although this was not statistically significant. The newborns had a t1/2 of 5.9 hours, compared to 2.5 hours in the older children. There was no statistically significant difference in distribution volumes or coefficients between the two groups of newborns who had an insignificantly higher relative apparent beta-phase distribution volume coefficient of 0.420 l/kg, compared to 0.377 l/kg in the older children. All had distribution coefficient values within the same range. The total body clearance in absolute terms, and when referred to body surface of 1.73 m2, was significantly lower in the newborns than in the older children, but the clearance, when referred to body weight, was of the same order in the babies and older children. The age differences affect dosage. Dosage schedules based on pharmacokinetics are proposed for gestationally premature babies, mature newborns, and older children. Premature infants can receive 2.5 mg/kg body weight and gestationally mature newborns 3.0 mgkg, both every 12 hours; the monitoring of serum concentrations is mandatory. Children aged three months and older can receive 3.0 mg/kg every eight hours.
We studied the response of Escherichia coli to ampicillin concentrations which decreased logarithmically at elimination half-life values (t1/2a) ranging from one to four hours. The rate of bacterial killing depended on the initial antibiotic concentration (co), but was not significantly affected by t1/2a. Irrespective of co and t1/2a, the bactericidal effect terminated after about three hours of exposure to the drug.
One hundred and seventy-seven Escherichia coli strains isolated from food, pigs and humans were tested for the production of heat-labile and heat-stable enterotoxin at 4, 22, and 37 degrees C. Heat-labile enterotoxin was detected in culture supernatants by an enzyme-linked immunosorbent assay, and heat-stable enterotoxin by the infant mouse bioassay. Thirty strains produced heat-labile enterotoxin, and twenty heat-stable enterotoxin. None of the strains isolated from food were enterotoxigenic. Fifty-seven per cent of the human and porcine strains producing heat-labile enterotoxin at 37 degrees C also produced the toxin at 4 degrees C. The fact that Escherichia coli enterotoxin may be present in food at consumption must be considered pathogenetically relevant.
The performance of four miniaturized biochemical test systems (API 20C Auxanogram, Mycotube, Oricult, and Uni-Yeast-Tek) for the identification of yeasts was evaluated using standard biochemical tests as reference. One hundred and twenty-six strains were used for the study. Mycotube identified 93% of the strains correctly, and Uni-Yeast-Tek 89%. API 20C Auxanogram and Oricult identified 77% and 82% of the strains respectively if the germ tube test was also included. Mycotube and Uni-Yeast-Tek in particular facilitate identification of yeasts in the routine clinical laboratory but recourse to microscopic examination of morphology and other supplementary tests may also be necessary.
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