Aage Mosegaard

Gentamicin and Gentamicin C1 in the Treatment of Complicated Urinary Tract Infections: Comparative Study of Efficacy, Tolerance, and Pharmacokinetics

The clinical efficacy, patient tolerance, and pharmacokinetics of gentamicin and the single component gentamicin C1 were studied after single and multiple doses in elderly male patients. Patient tolerance was extremely good at the dose levels used. There was some evidence of renal function impairment due to repeated intramuscular doses of gentamicin, but not gentamicin C1. The antibiotics were equally effective against the organisms present in the urine of these patients. The pharmacokinetics of the two antibiotic forms were similar, although gentamicin C1 appeared to have a larger distribution space.

Sisomicin Treatment of Complicated Urinary Tract Infections: Efficacy, Tolerance and Pharmacokinetics

From the Section of Urology, Veterans Administration Hospital; Department of Surgery, School of Medicine; and the School of Pharmacy, University of Wisconsin, Madison, Wisconsin. In the presence of serum, sisomicin appears to be more bactericidal than gentamicin and has been shown to be two to four times more effective in protecting mice from pathogenic bacteria. Comparative studies of the effects on renal function in the dog, cat, and rat suggest that 1H2 sisomicin is as toxic as or slightly more toxic than gentamicin.’ The purpose of the present study was to investigate serum levels of sisomicin in hospitalized male patients after single and multiple doses of 0.5, 0.75, and 1.0 1H2 mg/kg body weight, and also to compare serum levels of this antibiotic obtained by a standard microbiological assay and by the enzymatic assay recently described for gentamicin and other aminoglycoside antibiotics.2 The effect of sisomicin on urinary tract infections was also investigated.

Treatment with sisomicin of complicated urinary tract infections in patients with varying degrees of renal function impairment, pharmacokinetics and dosage adjustment.

SummaryThe efficacy, tolerance and pharmacokinetics of the new aminoglycoside antibiotic sisomicin, have been studied in 29 elderly male patients with varying degrees of renal function impairment and suffering from complicated urinary tract infections. The antibiotic was equally effective in patients with normal and impaired renal function and a cure (negative urine culture at one week follow-up) of 56% was obtained. There was little apparent toxicity with the dosage regimens used, although serum creatinine values were statistically but not clinically significantly increased in some patients following treatment. Serum half-lives of sisomicin were prolonged in cases of impaired renal function but accumulation of antibiotic could be prevented by varying dosing intervals between 8 and 24 hours based on serum creatinine values. There was good correlation between serum creatinine and sisomicin serum half-life values and a practical method is described for dose adjustment based on the relationship between serum half-lives and serum creatinine concentrations.ZusammenfassungDie Wirksamkeit, Verträglichkeit und Pharmakokinetik des neuen Aminoglykosid-Antibiotikums Sisomicin wurde an 29 älteren männlichen Patienten mit unterschiedlichen Graden der Nierenfunktionsstörung untersucht, die an komplizierten Harnwegsinfektionen litten. Das Antibiotikum war bei Patienten mit normaler und gestörter Nierenfunktion im gleichen Maße wirksam und in 56% der Fälle wurde eine Heilung erzielt (negative Harnkultur bei der Kontrolluntersuchung nach einer Woche). In den angewandten Dosierungen zeigte sich nur eine unbedeutende Toxizität, obgleich bei einigen Patienten die Serumkreatininwerte im Anschluß an die Behandlung statistisch, jedoch nicht klinisch signifikant erhöht waren. In Fällen von Nierenfunktionsstörung waren die Halbwertszeiten von Sisomicin im Serum verlängert, doch konnte eine Kumulation des Antibiotikums durch Variieren der Dosierungsintervalle zwischen 8 und 24 Stunden auf der Grundlage der Serumkreatininwerte verhindert werden. Es bestand eine gute Wechselbeziehung zwischen den Serumkreatininwerten und den Halbwertszeiten von Sisomicin im Serum und es wird eine praktische Methode zur Anpassung der Dosis auf der Grundlage des Verhältnisses zwischen Halbwertszeiten im Serum und Kreatininkonzentrationen im Serum beschrieben.

Treatment of complicated urinary tract infections. Comparative study of sisomicin and gentamicin.

The efficacy and safety of the two aminoglycoside antibiotics, sisomicin and gentamicin, were investigated in a prospective randomized study of 100 elderly male patients with complicated urinary tract infections. Both drugs were administered intramuscularly, sisomicin twice daily and gentamicin three times daily according to body weight. All bacteria isolated from the urine were sensitive to both antibiotics by disk sensitivity method. Seventy per cent of the patients treated with sisomicn and 63 per cent of those treated with gentamicin were cured of infection. There was no apparent toxicity noted from either drug. The twice daily sisomicin administration appeared to be as effective and safe as the three times daily administration of gentamicin in the treatment of complicated urinary tract infections.

Pharmacokinetics of 125I-iothalamate and 131I-o-iodohippurate in Man

The pharmacokinetics of 125I-iothalamate (IOT125I) and 131I-o-iodohippurate (OIH131I) have been studied in patients with varying degrees of renal insufficiency. Both compounds have been shown to obey two-compartment model kinetics after intravenous administration. The clearances are closely related to renal function, but poor correlations were obtained between renal function and compartmental distribution characteristics. This study provides further evidence that IOT125I and OIH131I may be used as indicators of renal function in patients after a single intravenous injection.

Trocar cystostomy during transurethral prostatic resection.

Abstract A new suprapubic trocar for constant drainage of irrigating fluid during transurethralresection of the prostate was studied in 87 patients: The irrigating fluid height was 60 cm. above the prostatic fossa in 61 patients and 40 cm. in 26 patients. The absorption of irrigating fluid during resection was measured by volumetric and radioisotopic methods and was compared with and without use of trocar in the two patient groups. In the 40-cm. group, but not in the 60-cm. group, the use of trocar cystostomy lowered the total as well as the intravascular absorption of irrigating fluid to low and clinically insignificant amounts. The low bladder pressure (average 8 cm.) explained the low absorption. The use of the trocar in this group also resulted in lower blood loss per gram resected tissue and less operating time per gram tissue removed. Use of the trocar in transurethral prostatic resection represents a technical advantage over conventional techniques, since it allows uninterrupted resection at a low bladder pressure.

Treatment of complicated urinary tract infections with sisomicin a comparison of once daily and twice daily dosage forms

SummaryIn the first part of this study the efficacy and tolerance of the new aminoglycoside antibiotic sisomicin administered intramuscularly 1 mg/kg body weight every 12 hrs was studied in the treatment of complicated urinary tract infections in 25 elderly male patients. The antibiotic was found to be well tolerated and effective, eradicating urinary tract infections caused by sensitive micro-organisms. In the second part of this study sisomicin administered intramuscularly once daily (75 or 100 mg) or twice daily (50 or 75 mg every 12 hr) according to body weight was evaluated in the treatment of complicated urinary tract infections in 24 elderly male patients randomized in two equal groups according to the dosage regimen. No significant difference in the tolerance and efficacy was found between the two groups. The cure rate in all 49 patients, defined as having a negative urine culture one week following treatment, was 75%. The sisomicin urine concentrations from 6 to 12 and even 12 to 24 hrs following the intramuscular injection was many times higher than the minimum inhibitory concentration for most gram-negative organisms commonly found in urinary tract infections. This probably explains the efficacy of the single daily dosage regimen which therefore can be recommended as effective and safe in the treatment of complicated urinary tract infections.ZusammenfassungDer erste Teil der Studie umfaßt die Überprüfun von Wirkung und Verträglichkeit von 1 mg/kg KG Sisomicin intramuskulär zweimal täglich verabreicht, bei komplizierten Harnwegsinfektionen von 25 älteren Männern. Das Antibiotikum wurde gut vertragen und beseitigte Harnwegsinfektionen durch empfindliche Keime. Im zweiten Teil der Studie wurde Sisomicin intramuskulär einmal täglich (75 mg oder 100 mg) bzw. zweimal täglich (50 mg oder 75 mg alle 12 Std.) entsprechend dem Körpergewicht bei 24 älteren Männern angewendet. Die Zuteilung zu den beiden Dosierungsgruppen erfolgte über eine Randomliste. Keine signifikanten Unterschiede in Wirkung oder Verträglichkeit fanden sich zwischen den beiden Dosierungsgruppen. Die Heilungsquote bei allen 49 Patienten, definiert durch eine negative Harnkultur eine Woche nach Ende der Behandlung, betrug 75 %. Die Harnkonzentrationen des Siomicin 6 bis 12 und sogar 12 bis 24 Std. nach der intramuskulären Injektion waren vielfach höher als die minimale Hemmkonzentration für die meisten gramnegativen Keime, die üblicherweise bei Harnwegsinfektionen gefunden werden. Das dürfte die Wirkung der einmal täglichen Dosierung-erklären, die deshalb als sicher und wirksam bei komplizierten Harnwegsinfektionen empfohlen werden kann.

Sisomicin treatment of complicated urinary tract infections

The purpose of this presentation is twofold: firstly, to present our experience with sisomicin in the treatment of complicated urinary tract infections; secondly, to summarize the results of our clinical trials with this antibiotic in patients with normal and impaired renal function, with particular reference to the determination of dosage and dosage intervals in cases of impaired renal function. We first treated 36 male patients (average age 71 years) with complicated urinary tract infection, but with normal renal function. These were divided into three groups of 12 each, with one group receiving sisomicin 0.5 mg/kg every eight hours, while the other two received 0.75 mg/kg and 1 mg/kg respectively every eight hours. Each group was treated for a total of seven days. Defining cure as a negative urine culture two to three weeks after cessation of antibiotic therapy, we obtained a cure rate of 50, 75 and 58% for the three respective groups. Sisomicin was well tolerated locally and systemically. In our second clinical trial we treated 29 males, all with complicated urinary tract infections, and again divided the patients into three groups, but this time according to renal function. Patients in Group A had a serum creatinine of 1.4 mg/ 100 ml, with an average creatinine clearance of 82 ml/min. Group B had a serum creatinine of 1.5 to 2.5 rag/100 ml and an average creatinine clearance of 34 mI/min, and Group C had a serum creatinine of 2.5 mg/100 ml and an average clearance of 18 ml/min. All patients received 1 mg/kg of sisomicin intravenously (IV) the first day, followed by 1 mg/kg intramuscularly (IM) every eight hours (Group A), every 12 hours (Group B) and every 24 hours (Group C) for seven days. Again sisomicin was well tolerated. It was equally effective in patients with normal and impaired renal function and a cure rate of 56% was obtained. The sisomicin urine concentrations up to 24 hours following a single IV injection in all three groups of patients were many times higher than the MIC values for most gram-negative organisms found in urinary tract infections. There was a good correlation between the sisomicin serum half-life and the serum creatinine level. The dosage intervals for administration of sisomicin in patients with normal renal function should be approximately eight hours, increased in azotemic patients by multiplying this interval by the serum creatinine (in rag/100 ml) or, if the dosage interval is kept unchanged, by dividing the dosage by the serum creatinine. Thus, a patient with a serum creatinine of 3 rag/100 ml would require 1 mg/kg every 24 hours. Since we found high sisomicin concentrations in the urine 8 to 16 and even 16 to 24 hours following IM administration, we proceeded to our next study in which we compared two groups of patients, again with complicated urinary tract infections, using two different dosages of sisomicin. One group received 75 mg of sisomicin every 12 hours, the other 100 mg every 24 hours. The cure rate, defined as a negative urine culture one week after treatment, was 75 % in both groups. In our last study we compared sisomicin with gentamicin in a prospective, randomized study of 100 patients with complicated urinary tract infections. Sisomicin (75 mg IM) was administered every 12 hours for seven days and gentamicin (80 mg IM), every 8 hours for seven days. Both groups were comparable in terms of age, other demographic factors, the urinary tract pathology and causative bacteria.