Ingrid Nilsson-Ehle

Age dependence of renal function: clearance of iohexol and p-amino hippurate in healthy males

Iohexol, a newly developed non-ionic contrast agent, has been recently documented as a reliable glomerular filtration marker. This study describes the age dependence of the single injection clearance of iohexol in a sample of healthy male volunteers ranging from 21 to 77 years of age. In parallel, renal plasma flow was studied by measuring the total clearance of p-amino hippuric acid administered as a continuous infusion. In subjects older than 50 years a negative correlation to age was found for both p-amino hippuric acid and iohexol clearance, with a reduction of 52 ml/min and 12 ml/min per decade, respectively, whereas no age dependence was found for younger subjects. Correlation between p-amino hippuric acid and iohexol clearances was 0.81. However, the filtration fraction, defined as the ratio of iohexol to p-amino hippuric acid clearance, was higher in the elderly subjects. A consistent discrepancy was found between total and renal clearances of p-amino hippuric acid, indicating significant renal metabolism. Renal clearance of creatinine was poorly correlated to iohexol clearance and did not show any relationship to age.

Influence of Ciprofloxacin on the Colonic Microflora in Young and Elderly Volunteers: No Impact of the Altered Drug Absorption

The colonic microflora was studied before, on the fifth day of dosing, and 2 weeks after a 5-day oral course of ciprofloxacin 500 mg BID given to 7 young and 7 elderly, healthy volunteers. Considerable changes in the aerobic microflora were found, while the effects on the anaerobic bacteria were less pronounced. Despite larger absolute bioavailability of the first dose in the elderly (77 vs. 63%; p less than 0.05), the effect of ciprofloxacin on the microflora was similar in the two groups of volunteers. A higher number of clostridia were detected in faeces from elderly subjects before, during, and after the ciprofloxacin regimen.

Magnetic Resonance Imaging in the Diagnosis of Spinal Epidural Abscess

In 3 patients with epidural abscess, 2 in the cervical spine and 1 in the lumbar spine the definite diagnosis was established by magnetic resonance imaging (MR). In 1 patient computerized tomography was performed but the correct diagnosis was revealed only by MR. The infections were all acute and due to Staphylococcus aureus organisms. One patient developed a tetraparesis on the third day, before the diagnosis was established or antibiotic treatment initiated. The other 2 showed only minor and passing neurologic deficits. None was subjected to laminectomy. In 2 cases the diagnosis was confirmed by puncture. None of the patients had a preceding trauma or a known focus for the staphylococcal infection.

Bactericidal Effect of Combinations of Antibiotic and Antineoplastic Agents against Staphylococcus aureus and Escherichia coli

Background: The bactericidal effect of some antibiotic and antineoplastic agents commonly used in clinical practice was investigated to analyse whether the combinations act synergistically, have indifferent or antagonistic antibacterial effects compared to the effect of the antibiotics alone. Methods: The rate of killing of meropenem, ceftazidime and tobramycin was studied against six different strains of Staphylococcus aureus and Escherichia coli, and the results were compared to the rate of killing of the antibiotics in combination with the cytostatic drugs doxorubicin, etoposide and 5-fluorouracil (5-FU). Results: Tobramycin showed synergy against two strains of S. aureus after 3 h in the presence of 5-FU and against one strain of S. aureus in the presence of doxorubicin. Meropenem induced an antagonistic bactericidal effect against one isolate of S. aureus after 24 h. Ceftazidime expressed an indifferent bactericidal effect together with the cytostatic agents. The antineoplastic agents had no impact on the bacterial killing of any of the antibiotics against E. coli. Conclusions: Tobramycin expressed a significantly better bactericidal effect against S. aureus after 3 h in the presence of doxorubicin and 5-FU than tobramycin alone. Meropenem expressed antagonism against one clinical strain of S. aureus, but the cytostatic drugs did not affect the killing of other strains tested. Ceftazidime expressed indifferent bactericidal activity together with the antineoplastic agents.

Pharmacokinetics of Ceftazidime in Febrile Neutropenic Patients

Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v. as a bolus injection over the course of 3 min. The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients. The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2Eight patients with fever and neutropenia were given 2 g of ceftazidime i.v. as a bolus injection over the course of 3 min. The pharmacokinetic variables for ceftazidime were similar to those found previously in febrile, acutely ill, non-neutropenic patients. The area under the plasma-concentration-time curve was significantly smaller, and the terminal half-life (t1/2lambda(z)) significantly shorter, compared with elderly, healthy subjects (p < 0.005). Three patients survived long enough to be assayed after normalization of temperature and neutrophil counts. Glomerular filtration rates and clearances tended to be higher and the area under the curve and half-life lower on the day of fever and neutropenia. When considering our data in relation to known MIC values for common pathogens, ceftazidime administered intermittently every 6 h seems an appropriate regimen in patients with febrile neutropenia. Larger studies are needed to confirm this.

Pharmacokinetics of meropenem in patients with cystic fibrosis.

Abstract The pharmacokinetics of meropenem were studied after single i.v. infusions of 15 mg meropenem/kg body weight in eight subjects with cystic fibrosis (CF) and eight healthy volunteers matched for age, sex, and weight. Significantly shorter terminal half-lives (mean, 0.74 h vs. 0.99 h) and mean residence times (mean, 1.09 h vs. 1.39 h) were noted in CF subjects. Plasma and renal clearances tended to be higher and distribution volumes smaller among the patients, but differences were not statistically significant. The results are consistent with the findings for many other beta-lactam agents used in CF patients. Assuming a MIC90 of 4 mg/l for meropenem against Pseudomonas aeruginosa, the time above the MIC was less than 3.3 h in six of the eight CF patients. This finding should be kept in mind when designing treatment regimens with meropenem in CF subjects.

Advancing age and acute infection influence the kinetics of ceftazidime.

The pharmacokinetics of ceftazidime were studied after single intravenous injections of 2 g in 10 healthy, elderly male volunteers (63-76 years old). None of the subjects were on concurrent drug treatment and all had normal age-correlated glomerular filtration rate. Mean values for major pharmacokinetic variables were: terminal half-life 2.63 h, area under the serum concentration curve 417.6 h mg/l, total clearance 74.6 ml/(min 1.73 m2), renal clearance 53.6 ml/(min 1.73 m2), urinary recovery/12 h 71.7% of dose and apparent volume of distribution (Vss) 15.0 l/1.73 m2. Data were compared with our earlier findings in studies of young male volunteers and elderly, acutely ill male patients. Advanced age was accompanied by a reduction in clearance of ceftazidime, while no significant age-related changes in distribution were noted. Acute infection was associated with increased Vss and enhanced renal clearance; alterations possibly caused by fever-induced changes in vascular permeability and renal blood-flow.

Pharmacokinetics of ceftazidime in elderly patients and young volunteers.

When given 2 g ceftazidime intravenously a group of 13 acutely ill but renally healthy, elderly patients demonstrated prolonged terminal half-life, increased area under the curve and reduced total and renal clearance compared to 9 young, healthy, male volunteers. The volume of distribution was enlarged in elderly males. Ceftazidime elimination correlated to renal function. Dosage twice daily for one week did not result in any clinically significant accumulation.

A randomized multicenter trial to compare the influence of cefaclor and amoxycillin on the colonization resistance of the digestive tract in patients with lower respiratory tract infection

SummaryEighty-four patients with lower respiratory tract infections participated in a randomised double-blind parallel multicenter trial in order to compare the efficacy of cefaclor and amoxycillin as treatment for lower respiratory tract infections and their ability to influence colonization resistance. Cefaclor was given to 40 patients and amoxycillin to 44 patients perorally in doses of 250 mg t.i.d. for seven days in a double-blind fashion. Sputum, oropharyngeal and intestinal specimens were taken for microbial analysis to isolate the causative pathogen of the lower respiratory tract infection and to follow the microflora changes before, during and after antibiotic treatment. The clinical outcome showed 92.5% cured or improved patients on cefaclor versus 88.4% on amoxycillin. The difference in clinical outcome between the two treatment groups was not statistically significant. Among the pathogenic bacteria isolated,Haemophilus influenzae, Branhamella catarrhalis andStreptococcus pneumoniae dominated. There was no difference between the two treatments with regard to microbiological efficacy. Treatment with cefaclor did not cause any significant impact on the oropharyngeal microflora. Administration of amoxycillin caused a significant reduction of the number ofStreptococcus salivarius andVeillonella cocci, while an increase in number of enterobacteria was seen in the oropharyngeal microflora. In the intestinal flora, cefaclor significantly reduced the number of streptococci, staphylococci and anaerobic cocci, while the number of enterococci, enterobacteria, bacteroides andCandida albicans significantly increased. The intestinal microflora was partly influenced by amoxycillin treatment. Thus there was a significant increase in the number of enterobacteria, anaerobic gram-positive rods and bacteroides. In conclusion, none of these agents caused any major disturbances in the colonization resistance in patients with lower respiratory tract infections.Zusammenfassung84 Patienten mit tiefen Atemwegsinfektionen wurden in einer randomisierten, doppelblind parallel geführten multizentrischen Studie mit Cefaclor oder Amoxicillin behandelt. Dabei wurde der Einfluß der Antibiotikatherapie auf die Kolonisationsresistenz untersucht. 40 Patienten erhielten Cefaclor, 44 Amoxicillin; die Dosierung betrug jeweils 250 mg dreimal täglich per os. Die Behandlung wurde sieben Tage lang durchgeführt. Vor, während und nach Antibiotikatherapie wurden Proben von Sputum, Abstriche aus dem Oropharynx und Stuhl entnommen. Die mikrobiologischen Untersuchungen dienten einerseits der Erregeridentifikation, andererseits der Verlaufskontrolle der Veränderungen der Mikroflora. Unter Cefaclor wurden 92,5%, unter Amoxicillin 88,4% der Patienten geheilt oder gebessert. Dieser Unterschied war nicht statistisch signifikant.Haemophilus influenzae, Branhamella catarrhalis undStreptococcus pneumoniae waren die häufigsten Erreger der Atemwegsinfektionen. In der Erregereradikationsrate unterschieden sich die beiden Therapien nicht. Unter Cefaclor traten keine wesentlichen Veränderungen der oropharyngealen Flora auf. Amoxicillin führte zu einer signifikanten Reduktion der Keimzahlen vonStreptococcus salivarius undVeillonella, die Enterobakterien nahmen in der oropharyngealen Mikroflora zu. Cefaclor führte zu einer signifikanten Verminderung der Keimzahlen von Streptokokken, Staphylokokken und anaeroben Kokken im Stuhl während Enterokokken, EnterobakterienBacteroides undCanadida albicans signifikant zunahmen. Auch Amoxicillin hatte zu Veränderungen der intestinalen Mikroflora mit Zunahme der Enterobakterien, anaerober grampositiver Stäbchen undBacteroides geführt. Stärkere Störungen der intestinalen Kolonisationsresistenz traten mit keiner der beiden Therapien auf.

Quinolone Disposition in the Elderly

SummaryThe fluoroquinolones are antibiotics frequently used in infections that affect elderly individuals. The physiological aging process can profoundly affect the pharmacokinetics of drugs, necessitating adjustment of dosage regimens in the elderly.Changes in pharmacokinetics with age are mainly due to the progressive deterioration of renal function, with resultant lower clearance of drugs which are eliminated by the kidneys. Ofloxacin is almost totally renally excreted and elimination is slower in older age groups; a dose reduction is therefore recommended for this quinolone.Unexpected alterations in pharmacokinetics may occur, as exemplified by the increased bioavailability of oral ciprofloxacin in elderly subjects. This is a well-documented phenomenon of such significance that lower oral doses are advisable for the elderly. Renal clearance of ciprofloxacin decreases in old age, but because of substantial nonrenal elimination the total clearance is affected less.Studies of the pharmacokinetics of the other quinolones in old age are scarce. No data exist on the absolute oral bioavailability of norfloxacin, enoxacin and pefloxacin. Renal clearance seems to be reduced, but since no intravenous studies have been reported, the total and nonrenal clearances are unknown in the elderly. No safe conclusions can be drawn regarding the necessity of dose reductions from a pharmacokinetic point of view. However, reports of adverse reactions to quinolones in the elderly, especially concentration-dependent symptoms from the central nervous system, and the risk of interaction with other drugs, suggest the need for caution in determining dosages of all of these compounds in elderly subjects.