Otoprotective Effect of Cortexin, Cogitum, and Elkar Administered Simultaneously with Netromycin in the Experiment.

We studied possible otoprotective effect of drugs widely used for the correction of perinatal hypoxic brain damage in premature infants. The experiments were carried out on immature rabbits with an immature hearing organ. The auditory function was assessed by DPOAE and ABR methods in intact animals and rabbits treated with therapeutic doses of netromycin alone or in combination with the drugs that normalize metabolic processes in the brain (Cortexin, Cogitum, Elkar, vitamin B2, ATP, and cocarboxylase). It was found that the administered drugs produced an otoprotective effect and reduced the severity, but did not eliminate the ototoxic effect.

Acquired Bartter-like syndrome association with netilmicin therapy in an extremely low birth weight infant.

Aminoglycosides are commonly used antibiotics with excellent renal parenchymal penetration. Their clinical effectiveness is counter balanced with the risk of renal toxicity, which develops in a dose-dependent fashion. Aminoglycoside-induced renal tubular dysfunction could result in diffuse damage or manifest as a Fanconi-like syndrome, Bartter-like syndrome (BLS), or distal renal tubular acidosis.(1-4) Although tubulopathy associated with amikacin and gentamicin was reported in adults and rarely children, to the best of our knowledge, netilmicin-associated BLS neither in adults nor in children has been reported in the literature. We here report a 30-week, 770 g male preterm infant who developed BLS just after netilmicin treatment for neonatal sepsis and recovered 6 weeks after the drug cessation.

Impact of metal ions on netilmicin-melanin interaction.

Netilmicin, which is mainly used as the sulfate, is a semisynthetic, water soluble aminoglycoside antibiotic obtained by chemical modification of sisomicin. It is active against both Gram-positive and Gram-negative bacteria, including strains which are resistant to other aminoglycosides. Netilmicin form complexes with melanin. The aim of the presented work was to examine the effect of Cu2+, Zn2+, Ca2+ and Mg2+ on netilmicin binding to synthetic DOPA-melanin. It has been demonstrated that metal ions decrease the amount of antibiotic bound to melanin as compared with netilmicin-melanin complexes obtained in the absence of metals. It has been also shown that only one class of binding sites participates in netilmicin-[melanin-metal ion] complexes formation with the association constant K approximately 10(3) M(-1). The obtained results demonstrate that Cu2+, Zn2+, Ca2+ and Mg2+ ions modify the interaction between netilmicin and melanin biopolymer. The blocking of some active centers in melanin molecules by metal ions, which potentially exist in living systems, may influence the clinical therapeutic efficiency as well as the undesirable side effects of netilmicin.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Tolerance of once-daily dosing of netilmicin and teicoplanin, alone or in combination, in healthy volunteers.

The purposes of this study were to test the pharmacokinetics and renal and otologic tolerances of a once-daily regimen of netilmicin and teicoplanin administered intramuscularly, alone or in combination (4.5 and 6 mg/kg, respectively), for 7 days in 30 healthy male volunteers. Teicoplanin induced only a mild increase in enzymuria. Nephrotoxicity was moderate and reversible with netilmicin; there was increased enzymuria and alteration in diluting ability, without significant changes in urinary beta 2-microglobulin levels, concentrating ability, and glomerular filtration rate. Ototoxicity was not detected in any of the subjects. Our results suggest that (1) teicoplanin and netilmicin given once daily induced only slight, reversible tubular damage, without any sign of ototoxicity; (2) their combination was not more toxic; and (3) clinical studies can be envisaged to evaluate the efficacy and tolerance of once-daily regimens in long-term treatment.

Clinical evaluation of netilmicin therapy in serious infections.

Netilmicin, a new semisynthetic aminoglycoside, was evaluated in the therapy of 33 episodes of infection in 30 patients. Eighteen patients had documented bacteremia. Infection sites included pulmonary, urinary tract and soft tissue areas. A complete bacteriologic and clinical cure rate of 85 per cent was achieved. No treatment failures occurred in the bacteremic group. Although netilmicin is less effective than gentamicin in vitro against Pseudomonas, it was clinically and bacteriologically effective. Netilmicin bacteriologic cures occurred in patients whose organisms were inhibited by 6.2 microgram/ml or less of netilmicin. Despite a uniform dosing protocol, a wide range of netilmicin serum levels was obtained. Adverse effects were limited to one case of transient nephrotoxicity and one Candida urinary suprainfection. Netilmicin appears to be an effective, safe agent for the therapy of serious infections.

Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone.

PURPOSE: Once-daily dosing of aminoglycosides has been suggested to improve their efficacy and reduce their toxicity. To test the clinical validity of this suggestion, we conducted a prospective, randomized trial comparing a conventional multiple-daily-dosing regimen of netilmicin with once-daily administration of the same total daily dose of this aminoglycoside. PATIENTS AND METHODS: We enrolled 141 predominantly elderly patients with severe bacterial infections. All patients received once-daily doses of 2 g ceftriaxone, in addition to netilmicin. RESULTS: Patients randomized to either of the two dosing strategies were comparable regarding age, APACHE II score, concomitant diseases, infection site, and rate of culture-proven bacteremia. Netilmicin treatment did not differ significantly in mean daily dose per kg body weight and days of therapy between the two treatment arms. Compared to patients receiving conventional doses, patients treated with a once-daily dose had higher serum peak netilmicin levels and lower trough levels. Outcome of infection and mortality were not influenced by dosing strategy. Although the overall incidence of nephrotoxicity was similar in both groups (16%), the occurrence of nephrotoxicity in patients treated with once-daily doses of netilmicin was significantly shifted to those given prolonged treatment, i.e., beyond 9 days. Auditory toxicity was documented in one patient treated with conventional doses and two patients treated with once-daily doses. CONCLUSION: Once-daily dosing of an aminoglycoside plus a long-acting cephalosporin in these patients constituted cost-effective and safe treatment for severe bacterial infections. Netilmicin-induced toxicity may be reduced by using once-daily dosing regimens and limiting the duration of treatment.

Prospective study of amikacin versus netilmicin in the treatment of severe infection in hospitalized patients.

PURPOSE: Four previous studies comparing netilmicin and amikacin have yielded inconclusive results concerning efficacy and rates of nephrotoxicity and ototoxicity. For this reason, we conducted a prospective, randomized, controlled trial of the two drugs in the treatment of hospitalized patients with severe infection. PATIENTS AND METHODS: A total of 202 patients were enrolled in the study; 100 received netilmicin and 102 received amikacin. Concomitant antimicrobials were restricted to metronidazole and benzylpenicillin. Peak and trough aminoglycoside levels were assayed within the first 36 hours and at least every 72 hours thereafter. A full blood cell count, serum electrolytes, creatinine, bilirubin, and liver enzymes were measured before therapy, weekly thereafter, and within 48 hours after the discontinuation of therapy. Nephrotoxicity and ototoxicity were assessed in patients. A standard agar dilution procedure was used to determine minimal inhibitory concentrations. RESULTS: No significant pretreatment differences were found between the two groups. Patients in the amikacin group responded significantly better to treatment than did patients in the netilmicin group (90% versus 79%; p less than 0.05). A notable finding was the markedly inferior response rate of Pseudomonas aeruginosa infections to netilmicin as compared with amikacin (13 of 24 with a favorable response compared with 25 of 26). No significant difference in ototoxicity was found, whereas nephrotoxicity appeared to be significantly less with amikacin (4% versus 12%, p less than 0.05). Although amikacin seemed less nephrotoxic than netilmicin, this may have been related to the significantly greater number of patients with initial renal dysfunction who received netilmicin. CONCLUSIONS: Amikacin appears to be significantly more efficacious than netilmicin for the treatment of P. aeruginosa infections, especially those in non-urinary tract sites. There is no apparent difference between the two drugs in terms of ototoxicity.

The aminoglycosides. Streptomycin, kanamycin, gentamicin, tobramycin, amikacin, netilmicin, sisomicin.

Despite their toxicity, the aminoglycosides remain useful and are often the first choice in the treatment of serious infections due to gram-negative bacilli. Nephrotoxicity has restricted the indications for neomycin to topical and oral use. Emergence of resistant organisms has limited the use of streptomycin to a few specific conditions. Gentamicin, tobramycin, and amikacin are effective against a broad spectrum of gram-negative bacilli including Pseudomonas aeruginosa. Amikacin is the aminoglycoside of choice when gentamicin resistance is prevalent.

A comparison of netilmicin and gentamicin in the treatment of pelvic infections.

Seventy-five women admitted with the symptom complex suggestive of pelvic inflammatory disease( PID) were started on a penicillin-aminoglycoside antibiotic regimen. An aminoglycoside, gentamicin or netilmicin (Schering-Plough), was chosen randomly and given parenterally. Forty-two patients received netilmicin and 33 received gentamicin for 5 days. Therapeutic response to the 2 antibiotic regimens was similar. Aminoglycosides have been associated with both nephrotoxicity and ototoxicity. Blood chemistries were studied in all patients. The only manifested toxicity was in 2 patients treated with gentamicin. Endometrial-endocervical cultures were obtained before and after therapy. The microbacteria isolated by standard culture techniques before therapy revealed Neisseria gonorrhoeae in 69% and 51% of the netilmicin and gentamicin groups, respectively; anaerobic organisms were cultured in about 75% of each group.

Netilmicin. A new aminoglycoside in the treatment of septic burn patients.

Netilmicin sulfate, a new aminoglycoside antibiotic, was administered to ten patients with thermal burns who were suffering from septic complications, usually burn wound sepsis. There were seven survivors. Eighty-three percent of all clinical isolates recovered showed sensitivity to the drug. No renal or auditory side effects were noted in any of the patients.

Comparison of once-daily and thrice-daily netilmicin regimens in serious systemic infections: a multicenter study in six Asian countries.

Patients with serious systemic infections admitted to eight medical centers in six Asian countries were treated with 300 mg of netilmicin given once daily (group A: 92 patients) or 100 mg of netilmicin given three times daily (group B: 93 patients). Netilmicin was administered by intramuscular injection or slow intravenous infusion until clinical, laboratory, and bacteriologic measures were normalized and for not more than two additional days. A clinical cure was achieved in 88% of the patients from group A and in 68% from group B. The causative micro-organisms were eliminated or infection site healed in 90% of group A and in 88% of group B. The mean treatment duration was 6.9 days in group A and 8.8 days in group B. Two patients in each group developed symptoms of nephrotoxicity; the pretreatment serum creatinine levels in all four patients were in the high borderline range. No other serious side effects were found. It is concluded that netilmicin administered once daily is safe and more effective than netilmicin administered three times daily.

Netilmicin in the treatment of Pseudomonas bacteremia.

The effectiveness of netilmicin was evaluated retrospectively in 40 patients with culture-documented bacteremia due to Pseudomonas aeruginosa. Netilmicin was the only antibiotic active in vitro against P aeruginosa that was administered to these patients. In 18 patients, Pseudomonas bacteremia developed in association with a Pseudomonas infection of the urinary tract; in 22 patients, Pseudomonas bacteremia developed from nonurinary or unknown sources. A clinical resolution or improvement was observed in 92% of the evaluable patients, and P aeruginosa was eliminated from the blood of 90% of the patients. The drug had nephrotoxic effects in two patients, but in no patient was there subjective or audiometric evidence of ototoxic effects. Three patients died during therapy. Based on these data, netilmicin is effective, and is associated with a low incidence of toxic effects, in the treatment of patients with Pseudomonas bacteremia.

Prospective, randomized comparison of the efficacy and safety of netilmicin-clindamycin and tobramycin-clindamycin in the treatment of serious systemic infections.

Fifty-three patients with documented or suspected mixed flora infections were randomly assigned to receive either netilmicin or tobramycin in combination with clindamycin. Data from 36 patients with 43 documented infections yielding 102 clinical isolates were evaluated for efficacy. In the 18 patients receiving netilmicin-clindamycin, 90% of the infections responded favorably and 96% of the pathogens were eliminated. In the 18 patients receiving tobramycin-clindamycin, 81% of the infections resolved and 88.5% of the pathogens were eliminated. Forty-nine patients were included in the safety analysis. The incidence of nephrotoxicity was similar in both groups (netilmicin, 20%; tobramycin, 21%). Auditory toxicity occurred less frequently in the netilmicin-clindamycin group (4.5%) than in the tobramycin-clindamycin group (21.7%). These results demonstrate that both the netilmicin-clindamycin and the tobramycin-clindamycin combinations are comparable in efficacy and in potential for causing nephrotoxicity. In this study, however, netilmicin was considerably less ototoxic than tobramycin.

Comparative clinical efficacy and safety of netilmicin and tobramycin in children with serious gram-negative infections.

Thirty children with serious gram-negative infections were treated with either netilmicin, 2 mg/kg, or tobramycin, 1 mg/kg, every eight hours for a minimum of 72 hours. Because of the administration of different doses, a "blind" investigator evaluated treatment response while another investigator adjusted the doses on the basis of each patient's drug serum levels and bacteriological response. Comparisons between the two study groups showed both treatments to be equally effective. All 15 patients treated with netilmicin and 14 of the 15 patients treated with tobramycin experienced complete resolution of clinical signs and symptoms and elimination of pathogens. One child in the tobramycin group was considered a treatment failure because of a persistent urinary tract infection. There were no adverse effects attributable to either drug.

Comparative evaluation of netilmicin-ticarcillin and tobramycin-ticarcillin in the treatment of serious systemic infections in elderly patients.

The effectiveness and safety of two antibiotic regimens, netilmicin-ticarcillin (NT) and tobramycin-ticarcillin (TT), were compared in a prospective, randomized, blind-evaluator study involving 60 elderly patients with serious systemic infections. Fifty-three patients were evaluated for treatment effectiveness; 25 (93%) of 27 patients in the NT group and 24 (92%) of 26 patients in the TT group had complete clinical resolution or improvement of their infections. There were two clinical failures in each group. Bacteriological responses were comparable in both treatment groups, with 87% (58/67) of the pathogens eliminated from patients in the NT group and 83% (59/71) eliminated from the patients in the TT group. The elimination rate for Pseudomonas aeruginosa, the organism most frequently isolated, was 88% (14/16) in the NT group and 77% (10/13) in the TT group. The differences between response rates of the treatment groups were not statistically significant. Auditory toxicity, detected by pure tone audiometry, was observed in two of the 24 patients treated with TT and in none of the patients treated with NT. Dizziness or vertigo, possibly resulting from aminoglycoside administration, occurred in one of the 29 patients given NT and in four of the 31 patients given TT. Nephrotoxicity, detected by serial serum creatinine determinations, developed in none of the patients in the NT group and in five of the 31 patients in the TT group, the difference being statistically significant (P = 0.05). The results of this study indicate that NT and TT are comparable in efficacy and that NT is less likely than TT to cause nephrotoxicity or disturbances in eighth cranial nerve function.

Prophylactic netilmicin in surgery.

Seventy-seven elective or emergency surgical patients were treated with a prophylactic course of netilmicin. Netilmicin (150 mg intramuscularly) was given 1 hour prior to operation and continued 12 hourly until the patient was free of risk of post-operative infection. There was no microbiological or clinical evidence of post-operative infection in general surgical or orthopaedic patients. Netilmicin seems to be less nephrotoxic than other aminoglycosides. Netilmicin serum levels were within expected values. Netilmicin was found to be an effective and well-tolerated antibiotic, and prophylactic treatment shortened the mean patient bed-stay and hence costs incurred.

Netilmicin sulfate: a comparative evaluation of antimicrobial activity, pharmacokinetics, adverse reactions and clinical efficacy.

Netilmicin, the 1-N-ethyl derivative of sisomicin, is a new aminoglycoside antibiotic that was recently marketed in the United States. Its role in therapeutics is not yet established. The pharmacokinetic profile of netilmicin is very similar to that of gentamicin. Its antimicrobial spectrum and clinical efficacy is similar to that of gentamicin, tobramycin and amikacin. It is less active in vitro against Pseudomonas aeruginosa that gentamicin and tobramycin, but in clinical trials the efficacy of netilmicin against the organism has been similar to other aminoglycosides. Netilmicin is active against some gentamicin and tobramycin-resistant strains of gram-negative bacilli, particularly those harboring adenylating and phosphorylation enzymes. Most of these strains are sensitive to amikacin as well, and amikacin is also active against most netilmicin-resistant strains of these bacteria. Therefore, amikacin remains the aminoglycoside of choice against gentamicin tobramycin and netilmicin-resistant gram-negative bacilli. In comparison to other currently available aminoglycosides, a lower frequency of nephrotoxicity and ototoxicity has been observed in laboratory animals given netilmicin. This has not been unequivocally demonstrated in humans. The frequency of nephrotoxicity in humans has been similar to that of other aminoglycosides. The frequency of ototoxicity associated with netilmicin in humans has been low but not significantly less than in other aminoglycosides, except in one trial. If further studies document a significantly lower frequency of ototoxicity with netilmicin, it may become the aminoglycoside of choice for patients with significant risk factors for ototoxicity, such as advanced age, renal impairment, concomitant ototoxic drug therapy and prolonged aminoglycoside administration.

Effectiveness and safety of once-daily aminoglycosides: a meta-analysis.

The effectiveness and safety of once-daily versus several-times-daily aminoglycosides were studied in a meta-analysis. MEDLINE for 1988 to 1995 was searched, and additional studies were identified from review articles and references in retrieved articles. Studies selected for meta-analysis were randomized controlled clinical trials in nonneutropenic adult patients comparing the clinical effectiveness or nephrotoxicity or ototoxicity of once-daily with several-times-daily aminoglycosides. Differences between groups were expressed as odds ratios. The results were combined by the procedure of Mantel and Haenszel, and 95% confidence intervals and exact confidence intervals were computed. An odds ratio smaller than 1 would indicate a lesser likelihood of a given endpoint in the once-daily group, and an odds ratio greater than 1 would indicate a greater likelihood. Eighteen studies involving 2317 patients were included in the meta-analysis. Summary odds ratios were 1.47 for effectiveness (95% CI = 1.13-1.94), 0.56 for ototoxicity (95% CI = 0.26-1.16), and 0.60 for nephrotoxicity (95% CI = 0.40-0.86). A meta-analysis showed that treatment with single daily doses of aminoglycosides seems to be more effective, less nephrotoxic, and as ototoxic as multiple doses daily.

Evaluation of distal tubular function in aminoglycoside-induced nephropathy.

Acute metabolic acidosis potentiates the nephrotoxicity of aminoglycosides by impairing the adequate excretion of ammonium and titratable acidity. The present study assesses distal tubular function after aminoglycoside administration in the rat. Two aminoglycosides, gentamicin and netilmycin were given to rats either in low doses equivalent to those used clinically (BG4 and BN5 groups) or in doses ten times higher (BG40 and BN50). The rats were subjected to acute metabolic alkalosis and the pCO2 of urine was continuously evaluated. The regression lines obtained by plotting the differences between urine and blood pCO2 as a function of urinary HCO3- in low dose models were similar to those obtained for the control group. However, the slopes obtained for BG40 and BN50 were significantly different from the control, suggesting an impairment of H+ secretion.