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

Abstract

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...

Treatment of Streptococcal Endocarditis with a Single Daily Dose of Ceftriaxone and Netilmicin for 14 Days: A Prospective Multicenter Study

“…This regimen was selected because ofthe pharmacokinetic properties of ceftriaxone [16] and the recent suggestions that a single daily injection of an aminoglycoside is just as efficacious as and possibly less toxic than multiple injections of the same total daily dose [6][7][8][9][10][11][12][13]. Of 48 assessable patients, 42 had their infections cured, five died during the follow-up period (none with evidence of active infection), and one relapsed.…”

“…Several clinical studies compared oncedaily to twice-or thrice-daily aminoglycoside administration, mostly in combination with ,B-lactam antibiotics; the two regimens were equally efficacious [6][7][8][9]. However, none of these studies included patients with infections for which the superiority of a combined regimen is as well established as it is in endocarditis.…”

“…This regimen has been used successfully on an outpatient basis and without a permanent iv catheter. Second, recent experimental and clinical evidence has suggested that administration of the total daily dose of an aminoglycoside in a single injection is as effective as administration of the same amount of drug in two or three injections and causes equal or less toxicity [6][7][8][9]. Indeed, in the treatment of experimental streptococcal endocarditis, when given in a single daily dose rather than as multiple doses, aminoglycosides were just as synergistic with ,B-Iactam agents such as penicillin and ceftriaxone [10][11][12][13].…”

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

“…versus that given t.i.d. at a daily dose of 6 mg/kg to patients with cancer and UTIs demonstrated a similar occurrence of cochleotoxicity in the two treatment groups (31).…”

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