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 anti-inflammatory effects of phenolic dental medicaments as determined by mouse ear edema assay.

The anti-inflammatory effects of phenolic dental medicaments were evaluated by mouse ear edema assay. p-Chlorophenol (PCP) inhibited edema when applied topically in dosages of 0.2 and 0.5 mg per site at 15 min before or 1.0 and 2.0 mg per site at 60 min after the application of croton oil. The inhibitory effects were also noted with eugenol, guaiacol, o-cresol, phenol and orally administered indomethacin (10 mg/kg). The involvement of the effects on prostaglandin biosynthesis in the anti-inflammatory effects of these compounds is discussed.

The role of EDRF in flow distribution: a microangiographic study of the rabbit isolated ear.

A microangiographic technique was used to study the influence of endothelium-derived relaxing factor (EDRF) on vasomotor control mechanisms in resistance vessels of intact buffer-perfused rabbit ear. Selective inhibition of EDRF activity by hemoglobin unmasked an intrinsic ("myogenic") constrictor response to sudden increases in flow rate. EDRF activity was greatest in arteries in which calculated shear stress and hydraulic resistance were maximal, namely the central ear artery and its first generation of branch arteries: these are proximal "feed" vessels (150-700 microns internal diameter) in this bed. The findings are consistent with enhancement of EDRF release by the physical stimulus of shear stress in resistance vessels as previously demonstrated in conduit vessels-a phenomenon which is likely to exert a major influence on flow in vascular networks. EDRF activity thus reduced perfusion pressure and power losses, particularly in highly constricted preparations. Shear-induced release of EDRF may provide an integrating link between flow and arterial topography by optimizing perfusion characteristics over a wide range of flow rates.

Ototoxicity of carboplatin in guinea pigs.

Since carboplatin (CBDCA) is a platinum compound of second generation, its ototoxicity was investigated. In order to assess the ototoxicity, hearing acuity was measured based on the compound action potential (AP), and the organ of Corti was morphologically studied using scanning electron microscopy (SEM) and succinate dehydrogenase (SDH) staining in guinea pigs treated with CBDCA. CBDCA induced morphological changes in the organ of Corti when the guinea pigs received 50 mg/kg daily for 2 or 3 days. The threshold value of AP was elevated 10 to 25 dB in treated animals, as compared with the control value. The SEM study and SDH staining revealed that the administration caused scattered degeneration of the outer hair cells (OHCs), and the inner hair cells remained intact. These lesions were milder than those of OHCs treated with cisplatin (CDDP). The rapid elimination of CBDCA from the kidney and the inner ear seems to account for the low ototoxicity of this compound. Although CBDCA is less toxic than CDDP, it may affect hearing function if patients suffer from renal dysfunction or if the organ of Corti is vulnerable.

Role of high-frequency audiometry in the early detection of ototoxicity. II. Clinical Aspects.

As a supplement to a previous paper [Dreschler et al.: Audiology 1985; 24:387-395] high-frequency (HF) audiometry was applied to compare the ototoxic effects of two different drug administration protocols for cis-platinum (CDDP). In both subgroups, HF audiometry considerably enhanced the early detection of ototoxicity. Marked differences between treatments have been established both in the pattern of onset of the damage and in the relation between dose and damage severity. For subjects treated with platinum derivatives, the thresholds at 12 and 14 kHz prove to be especially important. The results suggest that for these subjects the measurement of only a single frequency may be considered: with a minimum of effort, most of the increased sensitivity for a complete HF audiogram can be obtained. Finally, the relation between threshold deteriorations above 8 kHz and threshold deteriorations in the conventional range of audiometric frequencies has been investigated.

Enhanced cis-platinum ototoxicity in children with brain tumours who have received simultaneous or prior cranial irradiation.

We report on four children who received cis-platinum simultaneously with, or in one case 10 months after, cranial irradiation and experienced exaggerated ototoxicity affecting all audible frequencies. The hearing loss was severe, affecting the critical areas for speech perception, and necessitated the provision of bilateral hearing aids. The audiograms of these patients are shown and compared to those of four children who had received cis-platinum as part of their treatment for neuroblastoma but without cranial irradiation. The precipitation of the exaggerated hearing loss with the administration of cis-platinum in one patient 10 months after finishing cranial irradiation suggests that care should be taken in the timing of cis-platinum administration in relation to concurrent or previous cranial irradiation.

[Comparative study of the administration of amikacin by intramuscular and intravenous routes in neonatal resuscitation]. / Etude comparative de l'administration de l'amikacine par voie intramusculaire et intraveineuse en réanimation néo-natale.

A study was carried out to determine amikacin blood levels in 44 neonates who were admitted to a Pediatric Intensive Care Unit. Amikacin was administered by intravenous or intramuscular route. The levels obtained with both methods were similar. The results of our study indicate that amikacin levels should be monitored in neonates to avoid toxic concentrations of this drug. On the basis of this study a new neonatal dosage schedule is proposed.

Comparison of the effects of phenoxybenzamine and uptake blockade on noradrenaline efflux from rabbit ear arteries evoked by field stimulation and propagated nerve impulses.

1. A comparison has been made of the effects of blockade of prejunctional alpha-adrenoreceptors and blockade of transmitter noradrenaline uptake in segments of rabbit ear arteries subjected to field stimulation or neuronally propagated impulses. 2. The relationship between evoked release and frequency of stimulation differed in artery segments subjected to field stimulation and those receiving propagated nerve impulses. However, the effectiveness of phenoxybenzamine in increasing stimulation-induced efflux of radioactivity decreased as the frequency of stimulation increased in artery segments subjected to either field stimulation or neuronally propagated impulses. 3. Blockade of neuronal and extraneuronal uptake had no effect on evoked efflux from field-stimulated artery segments but it did produce a marked and significant enhancement of release evoked by propagated nerve impulses.

High-performance liquid chromatographic determination of netilmicin in guinea-pig and human serum by fluorodinitrobenzene derivatization with spectrophotometric detection.

A high-performance liquid chromatographic procedure for netilmicin determination in guinea-pig and human serum using pre-column derivatization with 1-fluoro-2,4-dinitrobenzene and UV detection is described. Linearity was established over the range 0.5-40 micrograms/ml using only 50 microliters of serum. Accuracy and precision were good, with a mean coefficient of variation less than 5% and a mean relative error less than 4%. This procedure correlates well with an enzyme multiplied immunoassay technique and has a sensitivity similar to those of published fluorescence derivatization methods.

The electrogenic Na-K pump does not contribute to endothelium-dependent hyperpolarization in the rabbit ear artery.

The application to smooth muscle cells of the rabbit ear artery, of either K ions after incubation with K-free solution, or of ACh produced a transient hyperpolarization of the membrane. Ouabain inhibited the former hyperpolarization but not the latter, indicating that the electrogenic Na-K pump possibly does not contribute to the endothelium-dependent hyperpolarization.

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.

Relative lack of systemic effects of mometasone furoate on Langerhans cells of mice after topical administration as compared with other glucocorticosteroids.

The effects of topically applied mometasone furoate were compared with those of other glucocorticosteroids, in particular fluocinolone acetonide, in assays of murine epidermal Ia+ Langerhans cell density. No evidence of systemic effects, as determined by a decline in the density of Ia+ LC in distant sites, was detected after local topical applications (5 times a week) of mometasone furoate 0.001% for periods of up to 3 weeks. Other steroids, even in such very low concentrations, and mometasone furoate in higher concentrations, produced systemic effects on Ia+ LC when used for longer than 5 d. The recovery time of Ia+ Langerhans cells is significantly shorter after application of mometasone furoate than after fluocinolone acetonide. However, with both compounds, recovery occurred more rapidly after 3 weeks than after a 1- or 2-week interval of compound administration.

Vancomycin ototoxicity and nephrotoxicity. A review.

Vancomycin has been in clinical use as a potent antistaphylococcal antibiotic for over 30 years. Most reports of ototoxicity and nephrotoxicity have been associated with early, relatively impure, formulations of vancomycin. This paper reviews the literature concerning vancomycin ototoxocity and nephrotoxicity and the evidence for their correlation with the therapeutic serum concentration range. There have been 28 reports of vancomycin-associated ototoxicity published in the medical literature since 1958. It remains unclear whether any diminution in hearing is permanent or reversible. Few patients in the literature had follow-up audiometry and the hearing impairment tends to be at higher frequencies. Several authors reported peak serum vancomycin concentrations, but the exact time these were drawn with respect to the last dose is mostly unclear. In other reports, the 'peak' concentrations noted 3 to 6 hours after the last dose are probably indicative of much higher concentrations because of vancomycin's rapid phase of distribution. More than half the 57 cases of reported nephrotoxicity due to vancomycin occurred within the first 6 years of the drug's use. Many of these patients also had pre-existing renal dysfunction or were concomitantly receiving other nephrotoxic agents. It is unclear whether the coadministration of aminoglycosides produces a synergistic toxicity. The exact incidence of nephrotoxicity is uncertain, but is probably less with the current, relatively pure, product. The correlation of nephrotoxicity with certain serum vancomycin concentrations remains to be clarified. Other aspects also require clarification, such as when to draw samples to determine peak serum concentrations and whether or not routine measurements are necessary at all. In the absence of better guidelines, efforts should be made to tailor individual patient's regimens to produce peak and trough serum vancomycin concentrations to within the widely accepted ranges of 30 to 40 and 5 to 10 mg/L, respectively. In addition, the concomitant use of other potentially nephrotoxic and ototoxic agents should be avoided.

Comparison of a radioisotopic incorporation method and the mouse ear swelling test (MEST) for contact sensitivity to weak sensitizers.

A radioisotopic incorporation assay utilizing [125I]iododeoxyuridine was compared to the standard mouse ear swelling test (MEST) for the strong sensitizers dinitrofluorobenzene and oxazolone, and for the three weak sensitizers ethylenediamine (EDA), glutaraldehyde, and nickel sulfate. Mice were sensitized epicutaneously on the abdomen for 4 consecutive days prior to challenging the left ear with the test agent and the right ear with the vehicle. A comparison of the mean difference between the test and the control ears showed that measuring reactivity 48 hr postchallenge on Day 7 is the most sensitive time period in the radioisotopic incorporation method. Both the isotopic and MEST assays gave positive results with the potent sensitizers, although the response detected by isotopic labeling of emigrating cells was up to 1000-fold greater than that determined by ear swelling measurements. No response was detected to the moderate to weak sensitizer EDA in either assay. Reactivity to glutaraldehyde was not detected by the radioisotopic assay but was minimally responsive and significant by the MEST. The opposite was true for nickel sulfate where minimal but significant reactivity was seen in the isotopic assay but not in the MEST. Although the radioisotopic assay had the advantages of being more quantitative and of having improved sensitivity, it was of no greater value than the MEST for detecting weak sensitizers. It was concluded that the mouse was not a suitable model for routinely detecting reactivity to weak sensitizers regardless of which of the two assays were used.

Vestibular reflex changes following aminoglycoside induced ototoxicity.

The effects of aminoglycoside-induced changes on the vestibular system were evaluated in three subjects who suffered significant damage over the course of treatment. Measurements of vestibulo-ocular reflex (VOR) function were made using sinusoidal and pseudorandom rotational stimuli between 0 to 5 days after initiation of drug therapy, during drug therapy, and up to 579 days following drug administration. All subjects tested at baseline evaluations had normal VOR function. During aminoglycoside therapy there was a precipitous drop in both the VOR time and gain constants. The decline in VOR function was larger at lower stimulus frequencies compared to high frequencies, resulting in a relative preservation of function in the high frequencies. Over a period of about a year, VOR high frequency gains recovered to within normal limits. However, the VOR time constants showed only a modest recovery and remained well below the normal range.