Hanne Colding

Pharmacokinetics of Amikacin During Hemodialysis and Peritoneal Dialysis

The pharmacokinetics of amikacin were examined in six bilaterally nephrectomized patients undergoing hemodialysis and in four patients with a minimal residual renal function undergoing peritoneal dialysis. The mean elimination half-life before the dialysis was 86.5 h in the anephric patients and 44.3 h in the patients with minimal residual kidney function. The results from the anephric patients suggest that some extrarenal elimination of amikacin may occur. The mean volume of distribution was about 25% of the total body weight. This is in accordance with values reported from subjects with normal renal function. During hemodialysis the half-life decreased to less than 10% (5.6 h) of the pretreatment value. The effectiveness of peritoneal dialysis was less as the half-life decreased to only about 30% (17.9 h) of the pretreatment value. During the dialyses a significant correlation between the half-life of amikacin and the decrease in blood urea and serum creatinine was demonstrated. The pharmacokinetic data were used to make dosage regimen recommendations for the treatment of patients undergoing intermittent hemodialysis or peritoneal dialysis.

Kinetics and dose calculations of amikacin in the newborn

The pharmacokinetics of a new aminoglycoside, amikacin, was evaluated in 37 infants between 1 and 34 days old. Fifteen were below 2,500 gm in weight. initial studies, including intravenous infusion in some of the infants, indicated that the disposition of amikacin was best described by a 2 compartment model. The absorption was evaluated in 8 of the infants after intramuscular injection of 7.5 mg amikacin per kilogram of body weight. The absorption rate, estimated by the tmax, was significantly faster than reported in adults. The total body clearance and apparent volume of distribution were studied in 22 infants after the same dose of amikacin intramuscularly. The body clearance expressed in relation to body surface or body weight was significantly less than in adults and correlated with the postnatal age. No correlation could be demonstrated between clearance and gestational age or birth weight. The volume of distribution per kilogram was significantly greater than in adults. On the basis of the derived kinetic parameters, a dose schedule is presented. In 5 children there was a reasonable agreement between the measured and predicted serum levels.

Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption

Regulated K+ transport across the plasma membrane is of vital importance for the survival of most cells. Two K+ channels have been identified in the Plasmodium falciparum genome; however, their functional significance during parasite life cycle in the vertebrate host and during transmission through the mosquito vector remains unknown. We hypothesize that these two K+ channels mediate the transport of K+ in the parasites, and thus are important for parasite survival. To test this hypothesis, we identified the orthologue of one of the P. falciparum K+ channels, PfKch1, in the rodent malaria parasite P. berghei (PbKch1) and examined the biological role by performing a targeted disruption of the gene encoding PbKch1. The deduced amino acid sequence of the six transmembrane domains of PfKch1 and PbKch1 share 82% identity, and in particular the pore regions are completely identical. The PbKch1-null parasites were viable despite a marked reduction in the uptake of the K+ congener 86Rb+, and mice infected with PbKch1-null parasites survived slightly longer than mice infected with WT parasites. However, the most striking feature of the phenotype was the virtually complete inhibition of the development of PbKch1-null parasites in Anopheles stephensi mosquitoes. In conclusion, these studies demonstrate that PbKch1 contributes to the transport of K+ in P. berghei parasites and supports the growth of the parasites, in particular the development of oocysts in the mosquito midgut. K+ channels therefore may constitute a potential antimalarial drug target.

Potentiation of the action of metronidazole on Helicobacter pylori by omeprazole and bismuth subcitrate

Treatment failures using triple therapy that include metronidazole, are common in patients infected with metronidazole-resistant Helicobacter pylori in the gastric mucosa. Higher eradication rates in such patients have been described when treatment regimens include bismuth salts compared to regimens that include proton pump inhibitors. In the present study, the synergistic effect of subinhibitory concentrations (0.25-0.5 MIC) of either bismuth subcitrate or omeprazole with metronidazole on the susceptibility of 42 H. pylori strains was investigated by agar dilution method and the Epsilometer test (Etest). With 0.5 MIC of either of the two drugs, the susceptibility of all H. pylori4 mg/l) reverted to being metronidazole sensitive. These results suggested that either bismuth salts or proton pump inhibitors may be effective in the treatment of some infections with metronidazole-resistant H. pylori strains when used in sufficiently high doses.

Enzymuria in neonates receiving continuous intravenous infusion of gentamicin.

Urinary excretion of the tubular enzymes NAG and AAP was investigated during gentamicin treatment of 105 newborn infants. The values found for NAG and AAP show a significant positive correlation. The urinary excretion of NAG was on the average 92% higher during gentamicin treatment as compared with non‐treatment periods in the same newborn infant (33 infants). The same tendency applied to AAP. Newborn infants receiving continuous intravenous infusion of gentamicin were not found to be at greater risk of nephrotoxicity than those receiving intermittent gentamicin treatment, using NAG and AAP as an index of nephrotoxicity. The changes in NAG and AAP within treatment periods were studied. During gentamicin treatment an insignificant average increase in the urinary excretion of NAG occurred, whereas a significant decrease was found during non‐treatment periods. A significant negative correlation was found between urinary excretion of NAG and birth weight/gestational age. The long‐term effect of the higher excretion of NAG and AAP in newborn and adult patients during aminoglycoside treatment is unknown.

Continuous intravenous infusion of ampicillin and gentamicin during parenteral nutrition to 36 newborn infants using a dosage schedule.

ABSTRACT. Ampicillin and gentamicin were given continuously i.v. to 36 newborn infants using a dosage schedule and the results were compared with those obtained in an earlier study including 88 infants who received individually calculated dosages. With the dosage schedule the variation in the serum concentrations of antibiotics was smaller in the same child throughout the treatment course, but greater between the infants. The 95 % limits for the serum concentrations of antibiotics were, however, nearly the same in the two treatment groups, and the use of a dosage schedule is therefore recommended. Serum gentamicin concentration should be assayed about 3 half lives (18 hours) after beginning the treatment, and dosage adjustment be made if the serum gentamicin concentration is outside 3–5 μg/ml.

Auditory Function after Continuous Infusion of Gentamicin to High-risk Newborns

ABSTRACT. Audiometry was performed at four years of age in 69 of 105 surviving children who had received continuous intravenous infusion of gentamicin during neonatal intensive care. A hearing loss of 20 dB was found in 2 of them (3 %), corresponding to that shown in other studies of survivors following neonatal intensive care. Free field audiometry performed in another 7 children and questionnaires returned from 13 of the remaining 29 gave no suspicion of hearing loss. Thus there is no indication that continuous 24 hours intravenous infusion of gentamicin causes more hearing impairment than intermittent intravenous or intramuscular administration.

Ribotyping of strains of Moraxella (Branhamella) Catarrhalis cultured from the nasopharynx and middle ear of children with otitis media

Moraxella (Branhaomella) catarrhalis is frequently present in the nasopharyngeal microflora of small children, especially during episodes of acute otitis media . By means of ribotyping (restriction endonuclease analysis of chromosomal DNA combined with rRNA probing), we studied the genetic heterogeneity of 78 cultures of M. catarrhalis obtained from different localities in the nasopharynx of nine young children with secretory otitis media. Using HindIII and PstI as endonucleases, five different ribotypes were recognized, representing at least five different genotypes of M. catarrhalis. The distribution of these types was found to be almost identical to the distribution among 16 M. catarrhalis strains cultured from middle ear exudates of 16 children with acute otitis media. Ribotype HAPA was found in two-thirds of all the cultures investigated, and 44% of the children harboured more than one ribotype in the nasopharynx at the same time. The vast majority of the nasopharyngeal M. catarrhalis cultures were beta-lactamase positive. One child had both a HAPA ribotype, beta-lactamase-negative strain in the nasopharyngeal secretions, and HAPA ribotype, beta-lactamase-positive strains at the entrance of the eustachian tube, the nasopharyngeal tonsils, the folds of the nasopharyngeal tonsils and the oropharynx. All except one of the M. catarrhalis strains cultured from middle ear exudates were beta-lactamase positive.

Stability of Antibiotics and Amino Acids in Two Synthetic l-Amino Acid Solutions Commonly Used for Total Parenteral Nutrition in Children

The stability and interaction at 29°C of ampicillin, carbenicillin, gentamicin, and polymyxin B were examined in a common electrolyte solution, invertose darrow, and in two synthetic l-amino acid solutions, one commercial (vamin with fructose; Vitrum) and the other a neonatal preparation modified for use in newborn infants. The concentration of amino acids was measured before and after the addition of these antibiotics. The concentration of antibiotics was measured over a 24-h period with a microbiological method. The concentration of ampicillin in invertose darrow fell 52%, and in vamin with fructose it fell 69%, whereas in the neonatal preparation the fall was only 22%. The concentration of carbenicillin in vamin with fructose fell 37%, and in the neonatal preparation it fell 31%. The combination of ampicillin or carbenicillin with gentamicin or polymyxin B did not influence the activity of the penicillins. The concentration of gentamicin and polymyxin B was unchanged in all solutions over a 24-h period. With the exception of cystine, the concentration of all amino acids remained constant after 24 h in the neonatal preparation with and without the different combinations of antibiotics. For cystine there was a fall of 20 to 30%.

Kinetics and dose calculations of ampicillin and gentamicin given as continuous intravenous infusion during parenteral nutrition in 88 newborn infants.

Ampicillin and gentamicin were administered continuously intravenously to 88 newborn infants using individually calculated dosages. For infants with a mean value of plasma clearance of the antibiotics, it was calculated that the serum ampicillin and gentamicin concentrations would be between 35-55 and 3-5 micrograms/ml, respectively, using the dosages for intermittent treatment. These dosages are therefore recommended as fixed dosages for continuous intravenous infusion initiated by a bolus dosage. Serum gentamicin concentration should be assayed about three half-lives after start of infusion and the dosage adjusted for values outside 3-5 micrograms/ml.