Article Eur. J. Clin. Microbiol.InfectDis., March 1990,p. 161-168 0934-9723190/03 016t-08 $ 3.00/0

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Prospective Randomized Study of Once-Daily versus Thrice-Daily Netilmicin Regimens in Patients with Intraabdominal Infections P. J. d e Vries 1, R. P. V e r k o o y e n 2, P. L e g u i t 3, H. A. V e r b r u g h 2.

One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netiimicin administered once daily (n = 98) versus thrice daily (n = 99) in combination with tinidazole administered once daily. Randomization was achieved for the infection site, clinical severity score, daily and total netilmicin dose, and duration of treatment. The mean maximum peak and trough levels of netilmicin in serum were 21.1 and 1.3 mgfl respectively for once daily treated patients, and 10.0 and 2.3 mg/i for thrice daily treated patients (p < 0.05 for both parameters). The clinical response did not differ between patients treated once daily and those treated thrice daily. Overall rates for clinical cure, improvement and failure of therapy were 77 %, 17 % and 6 % respectively. No significant differences were found between once daily and thrice daily regimens in the occurrence of auditory, vestibular and renal toxicity, overall rates being 5 %, 1% and 10 % respectively. Impairment of renal function was significantly related to higher maximum netilmicin serum trough levels during therapy, a higher clinical severity score and advanced age. It is concluded that netiimicin given once daily is as effective and safe as the multiple dose regimen. However, monitoring of aminoglycoside serum through levels is still advisable, especially in the old and severely ill patient.

Aminoglycosides such as netilmicin are frequently used in the treatment of serious infections in spite of their well known toxic potential and the availability of new, less toxic drugs with comparable activity (1-4). Thus intraabdominal infections are commonly treated with a combination of an aminoglycoside and an agent that is active against anaerobic bacteria. It has recently been suggested that the toxicity of amin0glycosides can be reduced, and perhaps their efficacy improved as well, if these agents are given only once daily (5). Compared to the conventional multiple daily dose regimen, a single infusion of the total daily dose will result in much higher serum peak levels and, after a 24-hour wash-out, reduced serum trough levels. Transiently higher aminoglycoside levels produce a more pronounced bactericidal effect in vitro (6, 7). Clinically, higher serum peak 1Department of Internal Medicine,2Departmentof Medical Microbiologyand 3Departmentof Surgery,Diakonessen Hospital, 1 Bosboomstraat, 3582 KE Utrecht, The Netherlands.

levels relative to the MICs of the infecting organisms have been associated with better response rates during aminoglycoside therapy (8). Data suggesting that once daffy administration of aminoglycosides is more effective have also been obtained in animal models (7, 9, 10). Prolongation of dose intervals also influences the toxic potential of aminoglycosides. Thus, aminoglycoside-induced nephrotoxicity has been correlated to persistently elevated serum trough levels but not to transiently high peak levels (9-12). Recent studies have shown that the rate of renal cortical uptake of gentamicin and netilmicin is limited and that, consequently, the accumultion of these drugs is less when given in one large daily dose compared to divided dose regimens (12, 13). To test the clinical validity of results obtained in laboratory and animal experiments, we undertook a large multicenter study comparing the efficacy and safety of once daily infusions of netilmicin versus netilmicin given in three divided doses in the treatment of patients with serious intraabdominal infections.

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Patients and Methods Patients. Seventeen hospitals in Belgium, the Netherlands and Luxembourg participated in the study. Adult patients 14 years and older with bacteriologically proven local or generalized intraabdominat infections including abscesses, and patients with gross peroperative intraabdominal spill of intestinal contents were eligible for enrollment in the study. Allergy to one of the drugs administered, severe preexisting renal impairment and/or hemodialysis, severe granulocytopenia (WBC < 1.5 x 109/1), progressive auditory or vestibular disease, administration of aminoglycosides within five days prior to enrollment, pregnancy and breastfeeding were exclusion criteria. Patients were stratified according to the site of infection and an Apache II derived clinical severity score accounting for the acute and chronic health status including age and renal function (14-17). Arterial pH, oxygen pressure, serum sodium and potassium concentration were not included since these data were not available for all patients. A high total score (on a scale of 0 to 54) indicated that the patient was severely ill.

Therapy Regimens. Patients were allotted at random to receive a treatment regimen by a computerized randomization table. Most of the patients underwent surgery and treatment was started peroperatively in such cases. Informed consent was obtained from all patients entered in the study. The netilmiein dosage was principally 6 mg/kg bodyweight i.v. for patients treated once daily and three times 2 mg/kg i.v. for patients treated thrice daily. Serum peak and trough levels were measured 30 rain after the end of administration and just before the next dosage, respectively, on days 1, 2, 3, 6, 9, 12 etc. For safety reasons accumulation of netilmicin to unacceptably high serum levels was avoided in both treatment groups. In the once daily group the serum trough level of netilmicin at 48 hours of therapy was not permitted to exceed 2 mg/l, otherwise administration of netilmicin was discontinued. In the group treated thrice daily, adjustments were made using conventional adjustment nomograms to achieve trough levels less than 2 mg/t and peak levels between 6 and t2 mg]l. Tinidazole was given in a dosage of 800 mg i.v. or 1000 mg orally once daily. Patients were treated for at least 48 hours. Bacteriological Investigations. Samples obtained from intraabdominal sites were transported immediately in evacuated syringes to the laboratory. Alternatively, specimens for culture were taken with sterile cotton swabs and transported in tubes containing transport medium designed to maintain relative anaerobiosis. Follow-up cultures of intraabdominal infection specimens were possible only in those patients who required surgery again due to clinical failure. All specimens were cultured under aerobic and anaerobic conditions. The sensitivity of all aerobic pathogens to netilmicin was tested by a conventional disk diffusion assay on agar plates, using disks containing 301.tg netilmicin. Inhibition zone diameters equal to or more than 14 mm were interpreted to indicate sensitivity, and zones less than 13 mm to indicate resistance.

Evaluation of Clinical Response. For the evaluation of efficacy only cases with positive cultures of an intraabdominal specimen were included. The clinical outcome was defined as recovery when all signs and symptoms of infection such as fever, leucocytosis and the presence of early leucocyte forms in the blood smear had disappeared. In these patients therapy was continued until they were afebrile for four consecutive days. Improvement was defined as clinical improvement without complete dis-

E u r . J. Clin. M i c r o b i o l . I n f e c t D i s .

appearance of signs and symptoms of infection after a period of treatment deemed to be adequate by the attending physician but exceeding at least 48 hours. In none of these cases was additional surgery for intraabdominal infection required. Clinical failure was defined as a persisting intraabdominal infection not caused by technical failure at surgery and leading to death or necessitating renewed surgery, or the spontaneous evacuation of an intraabdominal abscess. Only severe wound infections with exudation of fluid or pus with positive culture results were scored separately, The outcome in patients with wound infection was classified as clinical improvement when there was no intraabdominal infection and as failure when persisting intraabdominal infection was also present.

Evaluation of Safety. The initial auditory function was assessed within four days after the start of therapy by pure tone. audiometry using a portable audiometer at the bedside. Within one week after cessation of therapy the test was repeated. The testing frequencies ranged from 250 to 8000 Hz. If doubtful results were obtained, audiometry was repeated in a soundproof room. Results were analysed in two ways. Firstly, significant loss of auditory function was defined as a decrease in the hearing threshold of at least 15 dB for at least two frequencies in one or both ears. Only patients in whom an initial audiogram as well as a posttreatment audiogram were available were eligible for evaluation of possible loss of auditory function. Secondly, all frequency thresholds were analyzed separately. The discrete values and differences between pretreatment and posttreatment thresholds were analyzed in relation to the patient and treatment characteristics. In the patients with reliable audiograms only after therapy, results were analyzed together with all the other posttreatment audiograms. Evaluation of vestibular function was done by means of questioning and physical examination; no reliable noninvasive technique was available to evaluate inner ear function in these sick patients. Renal function was assessed by monitoring serum creatinine levels before therapy, at least every three days during therapy and after therapy (18). Results were analyzed in two ways, analogous to the procedure for auditory function. Firstly, patients were grouped and analyzed using a definition of nephrotoxieity as an increase in the serum creatinine level to exceed 150 % of the value at the start of therapy. Secondly, the course of the serum creatinine levels in all patients was evaluated and the maximum creatinine value reached during therapy and the time at which this occurred were analyzed.

Analysis of Findings. Clinical results and adverse reactions were analyzed in relation to the patient characteristics, diagnosis and treatment characteristics, including dosage regimen, Serum creatinine was recalculated as a percentage of the median of the normal range for every institute participating in the study. For comparison of the two treatment groups, Student's t-test or a non-parametric Mann-Whitney test was used for continuous variables, and a chi-square or Fisher exact test for discrete variables. Simultaneous analysis of several factors was done by analysis of variance, and the outcome within each treatment group was analyzed using a paired t-test of the Wilcoxon test. All tests were two-sided. Differences were considered to be statistically significant at p < 0.05.

Results Patients, A l t o g e t h e r 211 p a t i e n t s w e r e a l l o t t e d to a treatment regimen using a computerized randomization table. Fourteen patients dropped

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out of the study. Five of these patients were treated for less than 48 h, two of whom died, in one patient a dosage error was made, and one p a t i e n t had r e c e n t l y received o t h e r aminoglycosides. In seven patients who were treated once daily the first serum netilmicin trough level e x c e e d e d 2 mg/1 and administration of netilmicin was therefore discontinued for safety reasons. These seven patients (five females and two males) were significantly older (average 68 years, p < 0.05), and had a significantly higher m e a n initial serum creatinine (145 % of the median of the normal range, p < 0.05). Their clinical severity scores did not differ (7.4) c o m p a r e d to the other patients treated once daily. On r a n d o m i z a t i o n of the r e m a i n i n g 197 patients, the two groups resulting were c o m p a r a b l e with r e g a r d to d e m o g r a p h i c features (Table 1) and diagnosis (Table 2). All t r e a t m e n t characteristics of both groups were also c o m p a r a b l e except the serum netilmicin levels (Table 3). The maximum serum netilmicin peak levels were higher in patients treated once daily than in patients treated thrice daily, and the maximum serum trough levels were lower. Patients treated once daily received on average a total dose of 5343 mg tinidazole, patients treated thrice daily 5289 mg.

Table 2" Clinical diagnosis in patients treated with once daily and thrice daily netilmicin regimens. No. of patients on treatment regimen Diagnosis or site of infection Appendicitis (gangrenous or perforated) Colon Biliary tract Gross peroperative spill with infiltrative colon carcinoma Postoperative infection Stomach, duodenum Small intestine Pancreas Liver abscess Gynecologic infection Bowel distal to peritoneal fold Unknown Total

Once daily

Thrice daily

40

31

20 16 8

23 20 5

3 1 4 0 1 1 1

9 4 3 1 0 0 0

3 98

3 99

Bacteriological Results. A l t o g e t h e r 470 pathogens were isolated from the initial cultures of the i n t r a a b d o m i n a l infection specimens. T h e organisms r e p r e s e n t e d the normal intestinal flora, with a predominance of Escherichia coli ( 3 1 % ) and Bacteroides spp. ( 2 2 % ) . T h e distribution of species and percentage of susceptibility were not related to clinical outcome.

Table 1: Characteristics of patients treated with netilmicin administered once daily or thrice daily. Treatment regimen Characteristic Number of patients Male/Female Age (years) Mean + SD Range Clinical severity score Mean + SD Range Percentage of initial serum creatinine a Mean + SD Range

Once daily

Thrice daily

98 55/43

99 50/49

51 -+21 14--86

53 + 22 15-95

7.5 + 5.3 0-28

7.9 + 5.5 0-21

99 + 25 55-251

104 + 47 51-400

apercentage of the median of the normal range.

All a e r o b i c p a t h o g e n s w e r e susceptible to netilmicin except the enterococci and aerobic streptococci, amongst which many netilmicinresistant strains were found (68 % and 85 % respectively). In eight cases aerobic grampositive cocci were isolated in pure culture, in four cases the microorganism being resistant to netilmicin. All these four patients r e c o v e r e d completely except one who developed a superficial wound infection. Resistance of anaerobic m i c r o o r g a n i s m s to tinidazole was not encountered (Table 4).

Efficacy. In 18 patients treated once daily and 23 treated thrice daily, including the six cases in which no clinical diagnosis was made, the diagnosis could not be confirmed by positive cultures and h e n c e these cases were not included in the evaluation of efficacy. A m o n g these patients there were fewer cases with a clinical diagnosis of colon diseases (n = 8; 8 %) and appendicitis (n = 8; 13 %) than in the complete group. The 13 patients with gross peroperative spill were all o p e r a t e d on for large infiltrating colon tumors with bowel obstruction. During o p e r a t i o n necrotic material and bowel c o n t e n t s spilled into the a b d o m i n a l cavity necessitating antibiotic therapy. Five of those cases were clinically not evaluable due to negative cultures. The eight cases with positive cultures all recovered completely. A diagnosis

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Table 3: Treatment characteristics of patients receiving netilmicin once daily or thrice daily. The

number of patients evaluated was 197, except in the case of maximum serum peak (n = 192) and maximum serum trough levels (n = 185). Treatment regimen Treatment characteristic Duration of therapy (days) Total dose (rag)

Daily dose (mg/kg/day)

Maximum serum peak (mg/I)

Maximum serum trough (mg/1)

mean SD range mean SD range mean SD range mean SD range mean SD range

Once daily

Thrice daily

P value

6,5 2.1 3-14 2594 1024 900-5600 5.6 0.8 2.1-7.1 21.1 8.1 8.2-50.0 1.25 1.8 0.03-11.0

6.6 2.8 3-19 2404 1135 800-7020 5.4 0.2 2.3-8.6 I0.0 4.4 4.3-31.9 2.25 2.5 0,05-16.2

NS

NS

NS

< 0.0005

0.002

Table 4: Aerobic and anaerobic bacterial species isolated from 156 patients with intraabdominal infections treated with netilmicin once daily or thrice daily. Figures in parentheses indicate percentage susceptible to netilmicin. Anaerobic organisms and fungi were not tested for susceptibility to netilmicin. Number of isolates Species Streptococcus spp. Enterococcus spp. Staphylococcus spp. Bacillus spp. Escherichia coli Proteus spp. Other Enterobacteriaceae Pseudomonas and Acinetobacter spp. Neisseria spp. Clostridiumn spp. Anaerobic gram-positive cocci Bifidobacterium spp. Veilonella spp. Bacteroides and Fusobacterium spp. Yeasts and fungi

Once daily 29 16 10 0 70 16 26 8 0 6 4 1 0 57 1

of cholangitis was made in three cases of biliary tract infection on the basis of physical signs and symptoms, blood test results and ultrasonography. The other 33 cases were all cases of cholecystitis with local peritonitis. One hundred and fifty-six cases of bacteriologically proven intraabdominal infections in 80 patients treated once daily and 76 treated thrice daily were evaluated (Table 5). No differences in clinical outcome were seen between the two treatment groups. Overall, 93 % of the patients treated once daily (95 % confidence limits:

(19 %) (45 %) (85 %) (100 %) (100 %) (90 %) (88 %)

Thrice daily 25 22 10 2 73 7 17 7 2 4 5 3 1 48 3

(11%) (18 %) (100 %) (100 %) (100 %) (100 %) (100 %) (85 %) (100 %)

84 %-97 %) and 96 % of the patients treated thrice daily (95 % confidence limits: 89 % 99 %) responded favorably with complete recovery or improvement. These patients were treated for a slightly shorter period in both treatment groups (6.5 versus 7.5 days in the whole group; p =0.055) and consequently received less netilmicin (2545mg versus 2663 mg; p = 0.7) and tinidazole (5169 mg versus 6048 mg; p = 0.04). Patients with a favorable clinical outcome (recovery or improvement) had a significantly lower clinical severity score

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Table 5: Clinical response in patients with culture-proven intraabdominal infection treated with netilmicin once daily or thrice daily. Figures in parentheses indicate cases of wound infection. Treatment regimen Clinical response Cure Improvement Failure Total

Total

Once daily

Thrice daily

P value

120 27 (17) 9 (2) 156

58 16 (11) 6 (1) 80

62 11 (6) 3 (1) 76

NS NS NS NS

at the start of therapy than those in whom therapy failed (7.0 versus 10.9; p = 0.001). The clinical response was not related, however, to diagnosis or to serum netilmicin trough or peak levels.

Safety. No significant differences were found between the two dosage regimens in the occurrence of adverse reactions. Overall, the rates of ototoxicity, vestibular reactions, nephrotoxicity and other adverse reactions were 5 %, 1 % , 10 % and 14 %, respectively. Two audiograms were obtained in 88 patients, one within the first four days of treatment and one after therapy, and in 43 cases an audiogram was obtained only after therapy. Only patients in whom two audiograms were performed were eligible for the evaluation of ototoxicity. The four patients with significant loss of auditory function had significantly higher maximum serum netilmicin trough levels than the patients without auditory loss (2.15 rag/1 versus 1.05 rag/l; p = 0.020), however the unequal distribution of one patient treated once daily and three treated thrice daily influenced the mean trough level. Ototoxicity was independent of the other patient or treatment characteristics. When the threshold values for every frequency were analyzed it was found that generally the audiograms improved during treatment. High threshold values in the initial as well as in the post-treatment audiograms were significantly related to high serum netilmicin trough levels and advanced age (p < 0.05). It should be noted that these two factors coincided. For the evaluation of vestibular function 180 patients were eligible. Only two patients, one in each group, complained of dizziness or vertigo whereby a causal relation to the test drug was considered possible. Nine patients treated once daily and eight treated thrice daily experienced renal toxicity. No difference was found between once daily and thrice daily patients, resulting in an overall occurrence rate of 10 %. These patients were significantly older (67 versus 51 years; p = 0.003), had a higher clinical severity score

(12.0 versus 7.3; p = 0.001), and higher serum netilmicin peak (19.8 mg/1 versus 15.1 mg/1; p = 0.017) and trough tevels (5.3 mg/l versus 1.5m mg/1; p < 0.001). In patients treated once daily the difference between the mean serum levels of nephrotoxic patients and other patients was 3.2 mg/1 for maximum peak levels and 3.5 mg/l for trough levels. In patients treated thrice daily these differences were 4.8 and 4.4 mg/1 respectively (Table 6). The increase in the cumulative percentage of serum creatinine indicating nephrotoxicity started slightly earlier in the group treated thrice daily. However, the mean duration of treatment was longer in patients with nephrotoxicity treated thrice daily compared to such patients treated once daily, although this was not statistically significant. If the arbitrary definition of nephrotoxicity is abandoned and the serum creatinine levels analyzed separately, no significant differences in the evolution of this value during therapy were found between the two treatment groups. There was also no difference with respect to the highest serum creatinine value and the day on which it was measured. Initial high values were related to high clinical severity scores. The increase in serum creatinine during therapy was not related to the clinical severity score. The initial serum creatinine value, the maximum value during therapy and the difference between these two values were also related to high maximum serum trough levels during treatment in both groups, but not to the maximum serum peak levels. No causal relation could be found in time between the rise of the serum creatinine and serum trough levels. No relation to other treatment or patient variables was found. Other less serious events such as elevation of serum liver enzymes (16 patients), and nausea and diarrhoea (2 patients) were seen, but a causative relation to the treatment drugs remained doubtful. One patient complained of headaches which were possibly related to the administration of netilmicin, one patient complained of hallucinations, and one case of severe thrombophlebitis was encountered. One lactating (but not breastfeeding) female

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Table 6: Effect of patient and treatment variables on the development of nephrotoxicity during once daily and thrice daily netilmicin treatment. Number of patients with presence or absence of nephrotoxicity Once daily regimen Thrice daily regimen Present Absent Number of patients Mean age (years) Mean clinical severity

9 69 t3

72 51 7

scorc

Mean duration of treatment (days) Mean maximum netilmicin peak (mg/1) Mean maximum netilmicin trough (rag/l)

Present Absent 66

82 52

11

8

8

Both regimens Present Absent 17 67

154 51

P value 0,003

12.0

73

0,t301

7.2

6.5

8.1

6.5

7.7

6.5

0,08

24.4

21.2a

14.5

9.7a

19,8

15.1

0,017

4.4

0.9a

63

1,9a

5.3

1.5

< 0,001

ap < 0.05.

e x p e r i e n c e d a sudden d r o p of lactation and g r e e n d i s c o l o r a t i o n of the milk, in which netilmicin was demonstrable in a concentration of 0.3 mg/1. No relation was found between these adverse reactions and the patient or treatment variables. W h e n all adverse reactions were compiled it was noticed that patients with one or m o r e adverse reactions had b e e n t r e a t e d significantly longer than patients without any type of adverse reaction (7.3 versus 5.6 days respectively; p = 0.001), and consequently had received more netilmicin (2843 versus 2080 mg; p = 0.002) and tinidazole. T h e difference in treatment duration between patients with and w i t h o u t a d v e r s e e v e n t s was seen in b o t h treatment groups in similar proportions.

Discussion

The results of this study show that single daily infusions of netilmicin are effective and safe in the treatment of serious intraabdominal infections. No disadvantages with respect to either clinical efficacy or toxicity could be dem o n s t r a t e d with the o n c e daily r e g i m e n compared to the conventional thrice daily infusions of netilmicin. The clinical efficacy of a once daily netilmicin dosage regimen is not simply based on its pharmacokinetic profile in man; on the contrary, the short serum half..life of aminoglycosides such as netilmicin will result in prolonged periods of serum concentrations below the MIC between the consecutive daily doses (6). Rather, the clinical efficacy of once daily netilmicin is p r o b a b l y based on the

increased rates of bacterial killing at the site of infection upon exposure to the much higher concentration of this drug following the single large daily dose (6, 7, 9, 10). This advantage is maintained over consecutive doses (6), and may thus leave smaller bacterial inocula for the host defenses to clear. In addition, higher levels of . aminoglycosides will result in prolongation of the so-called postantibiotic effect that is seen on use of these drugs. T h e term postantibiotic effect refers to the recovery time needed by the bacterial p o p u l a t i o n surviving the initial exposure to aminoglycosides; this recovery period is associated with bacteriostasis, i.e. tack of multiplication, which may last up to ten hours in vitro (19) and up to 24 hours in animal models (7, 20). Other clinical investigators have used once daily dosage regimens of netilmicin and other aminoglycosides in the treatment of u r i n a r y t r a c t i n f e c t i o n s (21, 22), pelvic i n f l a m m a t o r y disease (23), g a n g r e n o u s and p e r f o r a t e d appendicitis (24), p u l m o n a r y infections in patients with cystic fibrosis (9), and s e r i o u s g e n e r a l i z e d i n f e c t i o n s (25; E . W . Ter Braak et al., 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, 1988, Abstract no. 558). In all these studies once daily regimens of aminoglycosides were comparable to or even better than thrice daily regimens with regard to efficacy and safety. In this study the evaluation of efficacy could have been confused by the fact that intraabdominal infection actually includes a variety of diseases (26). For this reason the patients in this study were stratified according to diagnosis and clinical severity score. Such stratification was not p e r f o r m e d in a previous

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study of patients with intraabdominal infections (24). The overall rate of treatment failure was somewhat higher in the present study than in the comparable study of Hollender et al. (24). However, these two studies differ in several aspects. Our patient group included substantially more cases of intraabdominal infection other than appendicitis, and the mean age of our patients was also much higher. In addition, patients were treated longer and with higher daily dosages. The number of patients experiencing hearing loss in our study was too small to provide substantial evidence that the netilmicin dosage regimen will influence the occurrence of ototoxicity. However, Tulkens et al. (23) noted significantly reduced rates of auditory toxicity among their patients, especially at audiofrequencies over 10,000 Hz. Impairment of vestibular function was seldom seen in our study. This was partly due to the technical difficulty of performing objective evaluation of vestibular function at the bedside of the recently operated patients. Since nephrotoxicity presents itself as a rise in serum creatinine, this parameter was used to monitor renal function in our study. Previously reported risk factors such as advanced age and severity of disease were found to be risk factors in both treatment groups in our study as in other studies (27, 28). Toxicity may also vary with the particular aminoglycoside under investigation. Thus netilmicin is probably less nephrotoxic than tobramycin and less ototoxic than tobramycin and amikacin (29). These differences in toxicity profile may in part be explained by differences in their rate of uptake by renal tubular cells and the ceils of the inner ear (12, 23, 30). Both the serum trough and peak levels were related to the occurrence of nephrotoxicity. However, the elevation of peak levels was quantitatively comparable to the rise in the trough levels, implying that there was no difference in the apparent volume of distribution. In accordance with previous reports, we found that only the height of the trough level seems to be a risk factor (11). This would favor the use of once daily administration with its prolonged wash-out period and lower trough levels. A relation in time, and hence a causal relation, between the elevation of s e r u m creatinine and trough levels could neither be confirmed nor disproved. However, monitoring of aminoglycoside serum levels did provide good feedback for dosage calculation, and therefore remains advisable. The almost complete absence of other serious adverse reactions is in line with results of previous studies. Elevation of serum liver transaminases is frequently observed in acutely ill patients but does not usually pose any clinical problems. The longer duration of treatment and higher total netilmicin dose in patients with one

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or more types of adverse reactions suggest a dose dependency. By evaluating the adverse reactions separately, this phenomenon may have been obscured by smaller numbers. Bias in scoring of the adverse reactions by the attending physicians seems less likely since most of the reactions were recorded as deviations of laboratory values. We conclude that our results support the hypothesis that the efficacy of aminoglycosides is not dependent on the time that serum levels exceed the MIC of the infecting organism. Rather, once daily administration of aminoglycosides such as netilmicin is at least as effective and as safe as thrice daily dosage regimens and may lead to more efficient usage of these drugs (31).

Acknowledgements

Statistical analysiswas performed by Prof. Dr. L. Kaufman, Dr. M. P. Derde, Department of Clinical Pharmacy,Free University,Brussels,Belgium. Participating physicians and their affiliations were_ C. Aelvoet, University Hospital Gasthuisberg, Leuven; W. Allegaert,St. Maarten Hospital,Kortrijk;R. J. Boskma, Rooms Katholiek Ziekenhuis, Groningen; G. Clyncke, St. Jans Hospital, Gent; P. Damas, Hbpital Sart Tilman,Liege; G. Glupczynski,H6pital Brujgmann,Brussels; C. Huvelle, Centre Hospital de Tivoli, La Louvi~re; M. Kox, G. Wagener, H6pital de la Ville, Esch-sur-Alzette; E. van der Linden, Middelares Hospital, Deurne; A. Mast, Heilige Familie Hospital, Gent; W. van Mieghem, Kliniek Andr6 Dumont, Waterschei; M. A. Muijsken, Stichting Samenwerking Delftse Ziekenhuisen, Delft; F. Roekaerts, Virga Jesse Hospital, Hasselt; L. J, Rutgeerts, Heilig Hart Hospital, Roeselare; A. W. Sturm, St. LaurentiusHospital, Roermond; J. P. Thys, H6pital Erasme, Brussels; P. J. de Vries, DiakonessenHospital,Utrecht. This study was supported by a grant from Essex-Benelux, Brussels.

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Prospective randomized study of once-daily versus thrice-daily netilmicin regimens in patients with intraabdominal infections.

One hundred and ninety-seven patients with intraabdominal infections were enrolled in a prospective randomized multicenter study of netilmicin adminis...
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