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.

Efficacy and safety of netilmycin/dexamethasone preservative-free and tobramycin/dexamethasone-preserved fixed combination in patients after cataract surgery.

PURPOSE: To compare the efficacy and safety of preservative-free Netilmycin/Dexamethasone with that of preserved Tobramycin/Dexamethasone, postcataract surgery. METHODS: Prospective, randomized, single-blind study on patients submitted to phacoemulsification. During preoperatory visits, at 7 and 21 days conjunctival hyperemia, corneal edema, Tyndall, Shirmer I, corneal and conjunctival lissamine green and fluorescein staining, and intraocular pressure (IOP) were recorded. Postoperative pain (at day 7) and the subjective tolerability (at day 21) were investigated. RESULTS: Eighty patients completed the study and the data collected were analyzed (44 on Netilmycin/Dexamethasone). Regarding the primary efficacy variable, intraocular inflammation, no microbial events were recorded, but aqueous flare was significantly lower with Tobramycin/Dexamethasone at 1 week (P = 0.002). Regarding secondary efficacy variables, conjunctival hyperemia was lower in patients under Tobramycin/Dexamethasone (P < 0.001), but corneal edema and ocular pain were similar. Regarding safety, no significant differences on ocular surface status were recorded. Both formulations were well tolerated, but Tobramycin/Dexamethasone caused an increased IOP at 1 week (P < 0.0001). CONCLUSIONS: Both the studied fixed combinations are safe and effective in controlling postoperative inflammation and preventing postoperative ocular infections. Tobramycin/Dexamethasone has a quicker anti-inflammatory effect but needs IOP monitoring. Further studies on more patients using a sounder scientific design are needed to confirm our findings.

Use of netilmicin once or twice daily in preterm newborns: evaluation of nephrotoxicity by urinary alpha1-microglobulin and retinol binding protein.

Since aminoglycoside efficacy is proportional to serum peak/MIC ratio and linked to post antibiotic effect, use of netilmicin once rather than twice a day has been proposed. On the other hand netilmicin might play a role in drug-induced nephrotoxicity, mainly on proximal tubule. Urinary retinol binding protein (RBP) and alpha1 microglobulin (alpha1m) are early and specific indicators of tubular damage and dysfunction. 21 preterm neonates (GA < 37 weeks) were divided in two groups on the basis of netilmicin administration modality (1: once a day, 2: twice a day, both for 7 days, at 5 mg/kg/die) and differences in netilmicin tolerability were assessed by evaluation of alpha1m and RBP levels by immunonephelometric method. No significant differences were found between the two groups either considering levels at time 1 and at time 2, or considering the difference between time 1 and 2 (Delta1/2). In our study once-daily dosing schedule shows similar low rates of nephrotoxicity, compared with multiple daily dosing schedule: this result may support the general adoption of once-daily dosing of netilmicin in clinical practice.

Dexamethasone-netilmicin: a new ophthalmic steroid-antibiotic combination. Efficacy and safety after cataract surgery.

PURPOSE: The purpose of this study was to evaluate both efficacy and safety of a new ophthalmic steroid-antibiotic fixed combination containing dexamethasone and netilmicin in the postsurgical management of cataract surgery. METHODS: In total, 223 patients were randomly treated with dexamethasone 1 mg/ml plus netilmicin 3 mg/ml (n=148), or dexamethasone 1 mg/ml plus tobramycin 3 mg/ml (n=75, TOBRADEX) four times in a day for 7+/-1 days starting immediately after surgery. Efficacy (anterior chamber (AC) inflammation, conjunctival hyperaemia, corneal and lid oedema, ocular infection, pain, photophobia and tearing) and safety (burning, stinging, blurred vision, intraocular pressure, and visual acuity) were analysed in the operated eye after 1 and 7+/-1 days. A follow-up visit was performed at day 14+/-2. The extent of AC inflammation, measured by slit-lamp according to a standard scoring system, was used as primary efficacy parameter. RESULTS: At the primary end point (day 7) both fixed combinations were equally effective in reducing postoperative inflammation. The safety profile of the dexamethasone/netilmicin combination was excellent with no evidence of poor local tolerance or adverse reaction. CONCLUSIONS: A new fixed combination of dexamethasone and netilmicin was effective and safe in controlling ocular inflammation after cataract surgery.

High local concentrations without systemic adverse effects after impaction of netilmicin-impregnated bone.

BACKGROUND: When cancellous bone is impregnated with antibiotics the subsequent release of antibiotics from the bone shows a high early release. Hence, impaction of large amounts of netilmicin-impregnated bone may cause toxic netilmicin values in serum. PATIENTS AND METHODS: We studied kidney and otovestibular function after impacting 50 g of netilmicin-impregnated cancellous bone during revision hip or knee arthroplasty in 20 patients. The bone was impacted in the acetabulum (n = 8), proximal femur (n = 9) and distal femur/proximal tibia (n = 3). Serum creatinine concentration was measured and audiometry was performed before and after the operation. Netilmicin concentrations in serum, joint fluid, and in urine were recorded postoperatively at regular intervals. We analyzed pharmacokinetics in two study groups receiving bone impregnated with netilmicin (50 mL), at either 50 mg netilmicin/mL (group I) or 100 mg netilmicin/mL (group II). RESULTS: Neither netilmicin-induced renal toxicity, nor otovestibular toxicity was registered. Peak serum netilmicin values in group I and group II were 0.9 (0.5-1.3) mg/L and 1.8 (0.6-4.0) mg/L, respectively (p = 0.04). Peak netilmicin concentrations in wound drainage fluid in group I and group II were 237 (9-647) mg/L and 561 (196-1132) mg/L, respectively (p = 0.01). In both groups, netilmicin was recovered in urine samples for approximately 4 weeks. INTERPRETATION: 50 grams of cancellous bone impregnated with 100 mg/mL netilmicin solution was impacted in the hip or knee joint with no adverse effects. Extremely high local concentrations of netilmicin in joint fluid were recorded postoperatively. The use of antibioitic-impregnated cancellous could be an option when performing revision of hip and knee prostheses.

Antimicrobial-induced endotoxaemia in patients with sepsis in the field of acute pyelonephritis.

BACKGROUND: In vitro results have shown that antimicrobial agents may induce the Gram-negative bacteria to release endotoxins (LPS), which in turn, could trigger the secretion of cytokines from monocytes. AIMS: To compare the effect of cefuroxime, netilmicin or ciprofloxacin on serum levels of LPS and tumour necrosis factor-alpha (TNFalpha). METHODS: Seventy-four patients with acute pyelonephritis caused by Gram-negative bacteria and signs of sepsis were randomly assigned to receive one of three intravenous regimens of cefuroxime, netilmicin or ciprofloxacin. Blood samples were collected before therapy and at specified time intervals for 96 hours after the initiation of treatment for the determination of serum levels of LPS and of TNFalpha. RESULTS: Patients treated with cefuroxime presented an early peak of LPS and of TNFalpha in serum two hours after the initiation of treatment compared to the other study groups. After that time interval, concentrations of LPS and TNFalpha were similar in all the study groups. Fever accompanied by endotoxaemia was still detected for 48 hours after the start of therapy in 36, 37.5 and 36% of patients treated with cefuroxime, netilmicin and ciprofloxacin respectively. The corresponding figures for these agents at 72 hours were 28, 12.5 and 24%, respective and 12, 4.2 and 4% at 96 hours (P value not significant). CONCLUSIONS: With the exception of an early peak in the serum levels of LPS and TNFalpha in patients treated with cefuroxime, no significant difference could be detected amongst the study groups as far as their effect on serum levels of LPS and TNFalpha were concerned. This suggests that these three antimicrobial agents may be administered safely at the early stages of sepsis.

Renal function and effect of aminoglycoside therapy during the first ten days of life.

The effect of aminoglycoside administration on kidney functional maturation was evaluated in groups of 30 preterm and 30 fullterm infants who were treated for 7 days because of suspected infection. One of three different aminoglycosides was administered to each subgroup of ten preterm and ten fullterm infants. Changes in tubular function in groups of ten preterm and ten fullterm infants who were not given antibiotics were also compared. The mean gestational age for preterm infants from 32.5 to 33.6 weeks and for fullterm infants between 39.2 and 39.5 weeks. The renal tubular function was assessed by examining the fractional excretion of sodium (FENa), potassium (FEK), phosphorus (FEP), magnesium (FEMg) and uric acid (FEUA) as well as by the urinary excretion of calcium as the calcium/creatinine (UCa/UCr) ratio. Gentamicin affected the normal plasma creatinine (PCr) decline in both treated groups (fullterm and preterm). Disturbances in FENa and UCa/UCr were more pronounced in treated preterm than in fullterm infants especially after netilmicin and gentamicin administration. FEMg was significantly affected in preterm infants treated with gentamicin. The findings of this study indicate that the effect of aminoglycosides on tubular function is dependent upon kidney maturity and the type of the aminoglycoside used for therapy.

Comparative cochlear toxicities of streptomycin, gentamicin, amikacin and netilmicin in guinea-pigs.

All the aminoglycoside antibiotics now in clinical use are ototoxic. This study was designed to compare the toxic effects of four aminoglycoside antibiotics, streptomycin, gentamicin, amikacin and netilmicin, administered to guinea-pigs systemically (at respective doses of 125 mg/kg, 50 mg/kg, 150 mg/kg or 37.5 mg/kg, twice daily for 1 week) or topically via the transtympanic route (0.25 ml/kg in 4% saline, twice daily for 1 week). Chosen doses were 10-20 times higher than the recommended human dosage. Cochlear damage was observed in all animals that were given systemic and local aminoglycosides. The severity of the cochlear damage was in the order gentamicin, amikacin, streptomycin, netilmicin, with gentamicin being the most toxic. No statistically significant difference between the severity of cochlear damage resulting from the systemic and topical applications was detected.

An open, randomized, multicentre study comparing the use of low-dose ceftazidime or cefotaxime, both in combination with netilmicin, in febrile neutropenic patients. German Multicentre Study Group.

To reduce drug acquisition costs, the clinical and bacteriological efficacy of low-dose ceftazidime i.v. (1 g tid) was compared with cefotaxime i.v. (2 g tid). Both regimens were combined with netilmicin i.v. (2 mg/kg bodyweight tid), in an open, randomized, multicentre trial in febrile neutropenic patients. The addition of antibiotics for gram-positive coverage was part of the protocol; alteration in the antibiotics for gram-negative cover or premature discontinuation of the study antibiotics were judged as failure. One hundred and eighty six patients were randomized by nine German centres, the patients matched for age, underlying diseases and duration of neutropenia (median duration 14 days) in both treatment arms. Infections were documented microbiologically in 29% of the patients, clinically in 16% and suspected (fever of unknown origin) in 102/186 patients (55%). The 82 pathogens isolated were predominantly gram-positive bacteria. In an intent-to-treat analysis, the overall response rate without modification at the final evaluation was 58% in the ceftazidime group and 34% in the cefotaxime group (P < 0.01). The success rates with modification were 84% and 64%, respectively. The failure rate in a highly immunosuppressed subgroup of the patients (bone marrow transplant recipients) was higher for cefotaxime (53%) than for the ceftazidime arm (14%) (P < 0.001). Response rates were significantly higher in the ceftazidime group for patients with microbiologically documented and possible infections. No major bacterial superinfections occurred in the low-dose treatment arm. The tolerability was good for both regimens. Low-dose ceftazidime combined with netilmicin proved to be superior to recommended doses of cefotaxime/netilmicin in febrile neutropenic patients.

[Once-daily dosage of aminoglycosides--a therapeutic simplification and an economical benefit]. / Dosering av aminoglykosider en gang i døgnet--en terapeutisk forenkling og et økonomisk fremskritt.

Conventionally, aminoglycosides have been administered in two or three daily doses. Numerous in-vitro and animal experiments and several clinical trials favour a once-daily dosage regimen of aminoglycosides, which provides a more rapid concentration-dependent bacterial killing and is probably less toxic than two or three dosage regimens. In this article the pharmacological and microbiological background for once-daily aminoglycoside administration is reviewed, and some controlled trials are discussed. Recommendations for clinical practice are given.

[A series of clinical study on netilmicin].

OBJECTIVE: To evaluate the clinical effects, pharmacokinetics, post-antibiotic effect (PAE) and toxicity of netilmicin as a single daily dose in the treatment of lower respiratory tract infection. METHODS: 48 cases were divided into 3 groups: In the first group, Netilmicin(6 mg.kg-1.d-1) was administered in a single daily dose; in the second group, netilmicin (200 mg/d) was combined with cefazolin (3 g, Q12 h); and in the third control group, the combination of cefazolin and Amikacin was used. Pharmacokinetics were studied in 7 patients using the TDX system, and PAE induced by Netilmicin was determined by the Avantage microbiologic system. Clinical symptoms, laboratory studies, chest X-rays, and side effects were observed. RESULTS: The overall clinical effects of the first group were better than those of the third group. The mean serum concentration of netilmicin was 27.23 mg/L, the valley serum concentration was 0.23 mg/L, T1/2 beta was 5.059 h, AUC was 70 micrograms.h-1.ml-1.netilmicin at concentrations 0.5, 1.0 and 4 times the MIC showed different degrees of PAE against 4 strains of bacterium. Nephrotoxicity and ototoxicity were not found in the treatment group. CONCLUSIONS: Netilmicin in a single daily dose resulted in a high peak serum concentration and big AUC. As a concentration-dependent bactericidal agent, netilmicin showed a longer PAE and better therapeutic effects.

Efficacy, safety, and tolerance of piperacillin/tazobactam compared to co-amoxiclav plus an aminoglycoside in the treatment of severe pneumonia.

An open, randomized, multicenter study was conducted to compare the efficacy and safety of piperacillin/tazobactam and co-amoxiclav plus aminoglycoside in the treatment of hospitalized patients with severe community-acquired or nosocomial pneumonia. Of the 89 patients who entered the study, 84 (94%) were clinically evaluable. A favorable clinical response was observed in 90% of the piperacillin/ tazobactam group and in 84% of the co-amoxiclav/aminoglycoside group (not significant). The bacteriological efficacy was comparable in both groups (96% vs. 92%; not significant). There was only one fatal outcome in the piperacillin/tazobactam group compared to six in the co-amoxiclav/aminoglycoside group regimen (P=0.058). The adverse event rate was non-significantly lower in the piperacillin/ tazobactam group compared to the co-amoxiclav/aminoglycoside group (2% vs. 7%; P=0.32). Piperacillin/tazobactam is safe and highly efficacious in the treatment of serious pneumonia in hospitalized patients. It compares favorably with the combination of co-amoxiclav/aminoglycoside.

Transient 5-oxoprolinuria (pyroglutamic aciduria) with systemic acidosis in an adult receiving antibiotic therapy.

5-Oxoprolinuria is a recognized condition with increased urinary excretion of 5-oxoproline and is associated with a variety of inborn metabolic defects involving the series of enzyme-linked reactions known as the gamma-glutamyl cycle. We report the unusual case of a 35-year-old woman who initially presented with staphylococcal pneumonia but went on to develop a transient high anion gap metabolic acidosis. The development and subsequent complete recovery from this acidosis were subsequently shown to be related in time to the intravenous administration of the antibiotics flucloxacillin and netilmicin. Analysis of the patient's urine for organic acids revealed massively increased excretions of 5-oxoproline at the peak of her acidosis. We suggest that this patient developed a transient disturbance in the gamma-glutamyl cycle involving the 5-oxoprolinase step, which resulted in accumulation of 5-oxoproline that caused a severe high anion gap metabolic acidosis. The administered antibiotics remain as possible causative agents.

Renal tolerability of four different once-daily dose regimen of netilmicin in critical care patients.

A prospective, randomized trial was conducted in a medical intensive care unit to assess safety and tolerability of four different dose regimens of intravenous netilmicin given once daily in the treatment of febrile episodes in critically ill patients. Eighty patients with febrile episodes during their stay in the intensive care unit were included in the study. The patients were randomized into four groups: Group 1 received a single daily dose of netilmicin based upon weight, age and renal function according to a dosage nomogram [13] (mean dose 298 +/- 29 mg, median 300 mg, range 250-350 mg), group 2 received 150% of this standard dose (mean 418 +/- 45 mg, median 400 mg, range 350-500 mg), group 3 200% (mean 525 +/- 41 mg, median 500 mg, range 400-550 mg) and group 4 250% (mean 710 +/- 39 mg, median 650 mg, range 600-750 mg). Duration of treatment was six days. Positive cultures were obtained in 29 patients. Serum creatinine and creatinine clearance, as well as netilmicin trough levels and levels of alpha 1-microglobulin showed no significant difference between the groups before, during, and after therapy. Our results indicate that with once daily dosing even high doses of netilmicin are well tolerated in patients with a creatinine clearance of > 70 ml/min before therapy. Necessary precautions include monitoring of drug trough levels (< 1 mg/L) and maintenance of adequate volume status.

Severe haemorrhagic diathesis in an adult patient with cystic fibrosis after long-term antibiotic treatment of pulmonary infection.

We describe the case of a 22 yr old male patient with cystic fibrosis, who, after long-term antibiotic treatment of pulmonary infection, developed a haemorrhagic diathesis with severe bleeding from the mucus membrane of the mouth, and haematuria. Rapid recovery was observed after infusion of vitamin K. During 8 months of follow-up, no evidence of recurrence of the clotting disturbances and anaemia were noted. The combination of impaired absorption of vitamin K due to underlying disease with the antibiotic-induced suppression of vitamin K synthesis by intestinal bacteria could be a possible explanation for this disorder.