Once daily administration of netilmicin compared with thrice daily, both in combination with metronidazole, in gangrenous and perforated appendicitis

The efficacy and safety of netilmicin, 5 mg/kg of body weight once daily or 2 mg/kg thrice daily for 10 days, for the treatment of gram-negative pyelonephritis in children were compared in a prospective, randomized trial. Explicit criteria were used to define the site of infection, treatment outcome, and adverse effects.Netilmicin was given to 74 children once daily and to 70 children three times daily. At 1 week posttreatment, 73 (99%) of 74 children treated with netilmicin once daily and 70 (100%) of 70 children treated with netilmicin three times daily were cured. At 4 weeks posttreatment, no relapse was detected and the rate of reinfection was essentially identical in the two treatment groups. Peak serum netilmicin concentrations were higher in patients given the once-daily regimen, whereas a higher trough level was detected in patients given the three-times-daily regimen. Nephrotoxicity, which was defined as an increase in the serum creatinine level of >0.3 mg/dl over the baseline, was rare (3%) and reversible and occurred regardless of the treatment regimen. Ototoxicity, which was assessed by pure-tone audiometry (250 to 8,000 Hz) and brain stem-evoked response (6,000 Hz), occurred in 2 of 32 children who were evaluated. In these two children, who were given the once-daily regimen, wave V was not evokable monolateraily below 25 and 40 dB normal hearing level, respectively. Thus, it may be possible to treat childhood pyelonephritis with netilmicin once daily. However

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“…This new approach to aminoglycosides dosing has been explored in preliminary studies with adults. In 1983, Powell et al (26) (13,29,31).…”

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confidence: 99%

Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children

Viganò

Principi

Brivio

et al. 1992

Antimicrob Agents Chemother

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“…(As recommended by Jablonski [13], we have used throughout this paper the abbreviations qd and tid to refer to the administration of the daily dose in one administration per day [quoque die] or divided in three equal administrations at 8-h intervals [ter in die].) Preliminary studies have suggested a similar clinical efficacy for aminoglycosides whether given qd, twice daily, or tid (9,18).…”

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confidence: 99%

Pharmacodynamic parameters and toxicity of netilmicin (6 milligrams/kilogram/day) given once daily or in three divided doses to cancer patients with urinary tract infection

Auwera

Meunier

Ibrahim

et al. 1991

Antimicrob Agents Chemother

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The pharmacologic parameters and toxicity of netilmicin (6 mg/kg/day) given once daily (qd) or thrice daily (tid) for the treatment of urinary tract infections were studied in a randomized prospective study of 60 cancer patients. The overall efficacy was 96%. Nephrotoxicity, assessed by the measure of urinary excretion of phospholipids, was lower for the patients receiving the qd regimen than for those receiving the tid regimen. Elevation of serum creatinine (20% over baseline) occurred in one patient receiving the qd regimen and in three receiving the tid regimen. Cochleotoxicity, assessed by pure-tone audiometry (250 to 18,000 Hz) occurred in one patient receiving the qd regimen and none receiving the tid regimen. Concentrations in sera were measured on days 1 and 5. No significant accumulation was observed in either group. Median serum bactericidal titers, expressed as reciprocal values (percentage of the sera with a titer .8), were measured against 25 test organisms in samples collected 6 h after the administration of netilmicin and were, for the qd group, 16 (82%) against members of the family Enterobacteriaceae and <2 (8%) against Pseudomonas aeruginosa, and for the tid group, 4 (57%) against members of the Enterobacteriaceae and <2 (0%) against P. aeruginosa. The rate of killing in serum was rapid (2 to 3 log in 2 h against P. aeruginosa; 3 to 5 log in 2 h against members of the Enterobacteriaceae) and correlated with the sampling time and hence the concentration in serum of netilmicin. The duration of the postantibiotic effect in serum depended also on the strain and the sampling time of the serum.Gram-negative infections are a major cause of morbidity in cancer patients, especially when they are neutropenic. Treatment of these infections consists of the administration of a broad-spectrum P-lactam antibiotic often in combination with an aminoglycoside. The use of combination therapy is advocated for infections due to Pseudomonas aeruginosa and is particularly important when microorganisms resistant to the 3-lactam antibiotic are responsible for the infection. A favorable outcome in patients with gram-negative bacillary bacteremia or pneumonia treated with aminoglycosides is related directly to the initial peak concentration in serum (20, 21) and to achieving a ratio of initial peak serum concentration to the MIC for the offending pathogen of greater than 6:1 (19). These observations confirm previous studies on the predictive value of the serum bactericidal titer on the outcome of gram-negative bacillary bacteremia (26,33). In addition, a prolonged postantibiotic effect (PAE) has been observed with aminoglycosides in vitro and in experimental infections (31,32). The main side effects of aminoglycosides are ototoxicity and nephrotoxicity (4,8,17,28). Studies in animals (1,11,16,23,34) have suggested that both nephrotoxicity and ototoxicity are lower when the daily dose is given as a single administration rather than in two or three divided doses over 24 h. A prospective study comparing netilmicin given onc...

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“…There have been at least 29 studies in humans, the majority being comparative clinical studies (tables III and IV). Although 22 studies were unable to show any difference in efficacy or toxicity related to the different (20) None Not tested appendixes [86] (metronidazole) Adults with appendicitis and other 114 N q24h (58); q8h (56) None None intra-abdominal infections [87] (metronidazole) Adults with intra-abdominal infections [88] 197 N (tinidazole) q24h (98); q8h (99) Adults with severe bacterial infections [89] a Dosage of aminoglycoside was 9.6 mg/kg for q24h therapy and 4.97 mg/kg for q8h therapy.…”

Section: Human Studiesmentioning

confidence: 99%

What is the Evidence for Once-Daily Aminoglycoside Therapy?

Barclay

Begg

Hickling

1994

Clinical Pharmacokinetics

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Aminoglycosides are important antibacterial agents for the treatment of serious infection. Evidence suggests that high peak plasma concentrations must be achieved early in the course of treatment if these agents are to be effective, but prolonged high concentrations may cause ototoxicity and nephrotoxicity. Peak plasma concentrations of 6 to 10 mg/L and trough concentrations of less than 2 mg/L for gentamicin and tobramycin have been traditional goals of therapy. Extensive recent evidence from in vitro, animal and human studies suggests that these target concentrations need revision. Aminoglycosides display concentration-dependent bacterial killing, have a long postantibiotic effect, and induce adaptive resistance in Gram-negative bacteria. All of these factors support the use of larger doses of aminoglycosides that are given less frequently than conventional therapy. Studies in vitro support this approach, showing greater activity when aminoglycosides are given less frequently. Animal studies comparing different dosage intervals have shown varying results, with only a slight bias favouring the longer dosage interval. However, the short elimination half-lives for the drugs in animals limit the applicability of these models to humans. Importantly, there is convincing evidence in animal studies that nephrotoxicity and ototoxicity are both reduced when the same total daily dose is administered in less frequent doses. There have been at least 29 clinical trials comparing once-daily administration of aminoglycosides with conventional administration 2 to 4 times daily. In general, efficacy has not been shown to be different between regimens, although one trial showed an advantage for once-daily administration compared with administration 3 times daily. A small number of trials have shown less nephrotoxicity and ototoxicity with once-daily administration, leading several authors to suggest that there is sufficient evidence to warrant a change to once-daily administration of aminoglycosides. However, once-daily administration has not been well studied in the paediatric population, or in patients with renal failure or endocarditis, and cannot be recommended in these patients as yet. The choice of a 24-hour dosage interval is somewhat arbitrary, and the optimal interval may not necessarily be 24 hours. No studies have included dosage adjustment based on pharmacokinetic modelling methods, and the effect of this on treatment outcome needs to be assessed. The best method of administering aminoglycosides once daily is yet to be determined.

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Once daily administration of netilmicin compared with thrice daily, both in combination with metronidazole, in gangrenous and perforated appendicitis

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Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children

Comparison of 5 milligrams of netilmicin per kilogram of body weight once daily versus 2 milligrams per kilogram thrice daily for treatment of gram-negative pyelonephritis in children

Pharmacodynamic parameters and toxicity of netilmicin (6 milligrams/kilogram/day) given once daily or in three divided doses to cancer patients with urinary tract infection

What is the Evidence for Once-Daily Aminoglycoside Therapy?

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