J Gen Microbiol, 1984 Mar, 130 ( Pt 3), 473 - 82 Resistance to apramycin in Escherichia coli isolated from animals: detection of a novel aminoglycoside-modifying enzyme; Hedges RW et al.; The mechanisms of resistance to apramycin of five isolates of Escherichia coli from animals were investigated . Three isolates, which were resistant to all the aminoglycosides tested, did not transfer their resistance and did not produce aminoglycoside-modifying enzymes . The fourth isolate, which was resistant to apramycin, tobramycin, gentamicin, kanamycin and neomycin but not to amikacin, owed its resistance to production of the acetyltransferase AAC(3)IV . The gene specifying this enzyme was carried on a transposon, Tn800, on a plasmid designated R1535 . The fifth isolate was resistant to apramycin, neomycin and kanamycin but not to gentamicin, tobramycin or amikacin . It produced an acetyltransferase that readily acetylated only apramycin, neomycin and paromomycin, a compound that is closely related to neomycin . Synthesis of this enzyme was specified by a chromosomal gene located near pyrD at about 20 min on the map of the E . coli K12 chromosome. J Chromatogr, 1984 Feb 10, 305(2), 345 - 52 An automated high-performance liquid chromatographic method for the determination of aminoglycosides in serum using pre-column sample clean-up and derivatization; Essers L; An automated high-performance liquid chromatographic method for the determination of the aminoglycosides amikacin, dibekacin, gentamicin, netilmicin, sisomicin and tobramycin is described . The procedure involves sample clean-up by adsorption of the aminoglycosides on a pre-column, subsequent derivatization with o-phthalaldehyde and on-line separation of derivatives by column switching . A short cation-exchange column serving concurrently as a guard column in combination with a reversed-phase column was used for separation . Except for the determination of netilmicin an internal standard consisting of an aminoglycoside was used in each assay . The signals of the aminoglycosides determined were linear within the range of 1-16 mg/l serum . The inter-assay imprecision (n = 10) calculated as coefficient of variation was less than 6% . The results were obtained within 20 min after injection of the serum sample . Easy performance and flexibility make the procedure feasible for therapeutic drug monitoring. Antimicrob Agents Chemother, 1984 Feb, 25(2), 168 - 72 Gentamicin, netilmicin, dibekacin, and amikacin nephrotoxicity and its relationship to tubular reabsorption in rabbits; Brion N et al.; The role of the tubular reabsorption of aminoglycosides in nephrotoxicity was considered . The tubular reabsorption rate, fractional reabsorption, and net balance, expressed as the excreted to infused aminoglycoside ratio, were concomitantly studied in male rabbits by continuous infusion of gentamicin, netilmicin, dibekacin, and amikacin . Aminoglycoside nephrotoxicity was evaluated by creatinine levels in serum and pathological renal damage after 14 days of a low- or high-dose regimen, comprising either eight, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (4 mg/kg) or amikacin (16 mg/kg); twelve, hourly intramuscular injections of gentamicin, netilmicin, or dibekacin (15 mg/kg) or amikacin (60 mg/kg); or injections of saline for the control group . Aminoglycosides exhibited three degrees of tubular reabsorption: gentamicin had the highest, netilmicin had the lowest, and dibekacin and amikacin had intermediate degrees of reabsorption . Nephrotoxicity associated with alteration in renal histology was observed with gentamicin and, to a lesser extent, with dibekacin in the high-dose regiment . No nephrotoxicity was noted with netilmicin or amikacin compared with the control group . Concentrations of the aminoglycosides in renal cortex and serum were not predictive of renal toxicity . Except for amikacin, which appeared to exhibit the lowest intrinsic renal toxicity, nephrotoxicity was correlated with the tubular reabsorption of each aminoglycoside . It was concluded that aminoglycoside renal toxicity can be determined by two major factors: importance of transport into tubular cells and intrinsic intracellular toxicity. Chemotherapy, 1984, 30(2), 69 - 75 Clinical application of amikacin dosage based upon lean body mass in patients with different renal function; Wagenvoort JH et al.; To determine an adequate dosage of amikacin, a pharmacokinetic model was used based on lean body mass (LBM), age and serum creatinine . Amikacin was administered during a mean period of 7 days to patients with normal (group I, n = 15, CCr greater than 60 ml/min), impaired stable (serum creatinine within a range of 50 mumol/l), (group II, n = 10) and unstable (group III, n = 8) renal function . The mean trough and peak blood levels were less than 2 and 24, 4.5 and 25 and 7 and 26 micrograms/ml in groups I, II and III, respectively . In group II and III a maximum trough level of 10 instead of 5 micrograms/ml was permitted to prevent a prolonged period of low subtherapeutic levels . With this modification the regimen in both groups appeared satisfactory . The pharmacokinetic model allows an accurate dosage regimen in all groups and can easily be programmed into a pocket calculator. J Infect Dis, 1984 Jan, 149(1), 23 - 30 Risk factors for the development of auditory toxicity in patients receiving aminoglycosides; Moore RD et al.; Risk factors for the development of auditory toxicity in patients receiving aminoglycosides were determined from the analysis of 135 patients enrolled in three prospective, randomized, double-blind clinical trials of gentamicin, tobramycin, and amikacin . Auditory toxicity, defined as a decrease in auditory acuity of greater than or equal to 15 dB, occurred in 30 patients (22.3%) . Patients with auditory toxicity underwent therapy for a longer period, were more likely to be bacteremic, and had, on the average, a higher temperature (P less than 0.05) . Using stepwise discriminant analysis, we selected these factors with liver dysfunction and the serum urea nitrogen:serum creatinine ratio in a function that accurately discriminates between toxic and nontoxic patients . Factors not adding significantly to the predictive accuracy of the equation were plasma aminoglycoside levels, aminoglycoside type, furosemide use, diabetes, age, sex, renal function, initial auditory acuity, hematocrit value, and shock . This analysis may be important both for determining the pathophysiology of auditory toxicity and for the prognostic stratification of patients receiving aminoglycosides in clinical trials. J Bacteriol, 1984 Jan, 157(1), 79 - 83 Cloning of the kanamycin resistance gene from a kanamycin-producing Streptomyces species; Nakano MM et al.; A kanamycin-producing strain, Streptomyces kanamyceticus ISP5500, is resistant to kanamycin . A kanamycin resistance determinant was cloned from S . kanamyceticus into Streptomyces lividans 1326, using the plasmid vector pIJ702 . The resulting plasmid, pMCP5, could also transform Streptomyces lavendulae S985 and Streptomyces parvulus 2283 to kanamycin resistance . Transformants carrying pMCP5 were markedly more resistant than S . kanamyceticus to the aminoglycoside antibiotics sisomicin, tobramycin, amikacin, and gentamicin . Studies in vitro polyphenylalanine synthesis showed that strains carrying pMCP5 contained kanamycin-resistant ribosomes . However, growing S . kanamyceticus contained kanamycin-sensitive ribosomes . Ribosomes from S . kanamyceticus grown under kanamycin-producing conditions were kanamycin resistant. J Fr Ophtalmol, 1984, 7(8-9), 539 - 43 {Penetration of amikacin into the anterior chamber of the human eye}; Barrera V et al.; The authors compared amikacin penetration into the aqueous humor after intraveinous and subconjunctival administration, by samples taken at cataract surgery . Of 12 patients divided into 4 groups, given 500 mg of intraveinous amikacin at one to four hours before surgery, none showed detectable aqueous levels; whereas, the plasma level was maximum at one hour (25.5 +/- 4.5 micrograms/ml) . Of 18 cases similarly divided into 4 groups given 30 mg of subconjunctival amikacin, aqueous levels of the drug were detectable at 24 minutes (6.2 +/- 5.2 micrograms/ml) and increased thereafter to 177.5 +/- 11.45 micrograms/ml at the maximum time allowed of 3 hours . No plasma levels were detected at time . Based on prior reports of the minimum inhibiting concentration of amikacin, subconjunctival administration would appear to provide effective aqueous levels for the prophylaxis and treatment of susceptable bacterial infections. Dev Pharmacol Ther, 1984, 7(6), 368 - 76 Effect of 'high-dose' amikacin in children; Kumor KM et al.; 17 children with serious infections were treated for an average period of 9.5 days with 420 mg/m2/dose of amikacin every 8 h . The nephrotoxicity and ototoxicity of this 'high-dose' regimen was studied . None of the children had evidence of nephrotoxicity . Of 9 children who could be clearly evaluated, 1 child experienced a delayed transient auditory dysfunction . 1 child experienced delayed serious deafness, but was receiving other ototoxic drugs . Despite the fact that the doses averaged 54.1 mg/kg/day, 5 children in our series had peak concentrations lower than that recommended for adults with serious infection. Ther Drug Monit, 1984, 6(3), 360 - 7 Clinical evaluation of the Abbott TDx fluorescence polarization immunoassay analyzer; Oeltgen PR et al.; The Abbott TDx fluorescence polarization immunoassay (FPIA) system was evaluated and compared with well-established enzyme multiplied immunoassay technique (EMIT) and radioimmunoassay (RIA) methods utilizing five high-volume drug assays including theophylline, gentamicin, phenytoin, phenobarbital, and digoxin . These drug assays were evaluated for precision, calibration stability, specificity, and accuracy . Within-run precision studies utilizing control samples (n = 20) in the subtherapeutic, therapeutic, and toxic ranges resulted in coefficients of variation (CV) of less than 4.0% for the theophylline, gentamicin, phenytoin, and phenobarbital assays and of less than 9.5% for the digoxin assay . Between-run precision studies based on an initial TDx calibration curve over a 2-3 week period yielded CVs of less than 8% for all five drug assays . Cross-reactivity of the FPIA gentamicin assay with concurrently used aminoglycosides such as tobramycin and amikacin was less than 0.1%, and interference due to hemolysis and lipemia was negligible . Highly icteric specimens resulted in clinically significant decreases in theophylline and phenytoin concentrations, but this problem can be corrected by subtraction of blank intensity values . Comparison of the FPIA method with the EMIT and RIA methods indicated an extremely good analytical correlation (r greater than 0.97) for all five comparisons . The Abbott TDx FPIA system offers significant advantages in calibration and reagent stability, and greater sensitivity in the low drug concentration ranges while maintaining accuracy and precision comparable with those of established EMIT and RIA procedures. Ann Biol Clin (Paris), 1984, 42(3), 217 - 20 Amikacin assay: correlation between rapid bioassay, enzyme immuno-assay (EMIT) and fluoro-immuno-assay (FIA); Damien JM et al.; Three methods (rapid bioassay, enzyme immunoassay and fluoroimmunoassay) for the determination of amikacin level in serum are compared . The statistical analysis of the results show correlation coefficients equal to 0.967 (EMIT versus FIA), 0.970 (bioassay versus FIA) and 0.983 (bioassay versus EMIT) . The three methods are acceptable for routine clinical use . The enzyme immunoassay adapted on a centrifugal analyzer appears to be a method of choice for laboratories with a large workload . However, the rapid bioassay described in this paper remains adequate for laboratories testing 5 to 10 sera per day. J Antimicrob Chemother, 1984 Jan, 13 Suppl A, 9 - 22 Aminoglycoside toxicity - a review of clinical studies published between 1975 and 1982; Kahlmeter G et al.; The present survey of aminoglycoside nephro- and ototoxicity covers approximately 10,000 patients reported on in clinical trials published between 1975 and 1982 . Included in the survey were clinical trials with at least 15 patients evaluable for nephro and/or ototoxicity provided relevant data were given on methodology, patient material and aminoglycoside dosage . Each publication was evaluated by both investigators and relevant data entered into a chart . One hundred and forty-four published trials were surveyed; 139, 63 and 34 for renal, cochlear and vestibular side effects, respectively . Frequencies were calculated as number of patients with side effect of total number of evaluated patients . In the average overall figures toxicity labelled by respective authors as 'definitely', 'probably' and 'possibly' related to study drug is included . When available, frequencies of toxicity 'definitely' and 'probably' related to study drug were analysed separately . The average daily dosages of gentamicin, tobramycin, netilmicin and amikacin were 3.9, 3.8, 5.2 and 15.4 mg/kg, respectively . The average frequencies of nephrotoxicity for gentamicin and tobramycin were 14.0 and 12.9%, respectively, and of netilmicin and amikacin 8.7 and 9.4%, respectively . The average frequency of cochlear toxicity was 13.9% for amikacin, 8.3 and 6.1% for gentamicin and tobramycin, respectively, and 2.4% for netilmicin . The material available for evaluation of vestibular toxicity was considerably smaller . The average frequencies for gentamicin, tobramycin and amikacin were similar (3.2 to 3.7%) while netilmicin again exhibited a somewhat lower figure (1.4%) . The overall figures and the clinical ranking that they imply were basically substantiated when prospective comparative trials were analysed separately . However, some inconsistencies go unexplained: for example the frequency of gentamicin nephrotoxicity was markedly higher in trials where it was compared to tobramycin (20 trials) than when it was compared to netilmicin (16 trials). Drug Intell Clin Pharm, 1983 Dec, 17(12), 906 - 8 Aminoglycoside inactivation by penicillins and cephalosporins and its impact on drug-level monitoring; Tindula RJ et al.; The degree of in vitro inactivation of gentamicin, tobramycin, and amikacin by various penicillins and cephalosporins was investigated . Serum samples were prepared that contained one aminoglycoside and one penicillin or cephalosporin . Each aminoglycoside was combined with each of the following: penicillin, ampicillin, nafcillin, carbenicillin, ticarcillin, cephapirin, cefazolin, cefoxitin, and cefamandole . Each sample contained a final concentration of 10 micrograms/ml of gentamicin or tobramycin, or 35 micrograms/ml of amikacin, with 400 micrograms/ml of the beta-lactam antibiotic . Control samples containing only the aminoglycoside were used for comparison . Half of each mixture was frozen at -20 degrees C and the remainder was left at room temperature for 24 hours . The samples were assayed for aminoglycoside content by a radioimmunoassay and each combination was compared with its control value . Based on the results, the beta-lactams can be divided into three groups: (1) cefazolin and cefamandole, which cause little inactivation; (2) nafcillin, cephapirin, and cefoxitin, which cause moderate inactivation; and (3) penicillin, ampicillin, carbenicillin, and ticarcillin, which cause marked inactivation . In general, tobramycin was the most reactive of the three aminoglycosides studied and amikacin the most stable . The frozen samples were much less affected than those left at room temperature . Freezing samples, if there will be a delay in assaying, and choosing aminoglycoside sampling times when the beta-lactam concentration is at a trough are recommended to minimize spurious aminoglycoside level determinations due to in vitro inactivation. J Antimicrob Chemother, 1983 Nov, 12(5), 481 - 8 Amikacin concentrations in serum and blister fluid in healthy volunteers and in patients with renal impairment; Lanao JM et al.; Following iv administration of 0.5 g of amikacin, the concentrations of the antibiotic were determined in serum and blister fluid of nine healthy volunteers and ten patients with renal impairment . In the former, the maximum concentrations of amikacin in blister fluid was 11.85 +/- 4.6 mg/l . The half-life in blister fluid was 2.39 +/- 1.10 h, slightly greater than that of serum (1.73 +/- 0.24 h) . The concentrations of the antibiotic in serum and blister fluid are modified significantly in patients with renal impairment . The half-life values in both fluids increase similarly, parallel to the reduction in renal function . The penetration of amikacin into blister fluid in these patients increases progressively and a linear relationship is established between the maximum concentration reached and creatinine clearance . A linear relationship has also been established between the concentration of the antibiotic in serum and blister fluid. Jpn J Antibiot, 1983 Nov, 36(11), 3277 - 82 {Therapeutic effects of micronomicin on experimental infections in mice by intravenous administration}; Sato K et al.; Protective effects of intravenous administration of micronomicin (MCR) on mouse experimental infections were investigated . Mice were better protected by intravenous administration in S . marcescens T-55 experimental infection than subcutaneous administration . No remarkable differences were found between the two administrations in cases of P . aeruginosa BMH No . 1 and E . coli GN 2411-5 infections . Intravenous administrations of MCR, gentamicin (GM), dibekacin (DKB), amikacin (AMK) and sisomicin (SISO) protected the infection of P . aeruginosa BMH No . 1 in a similar extent . MCR was more effective intravenously than AMK; DKB and AMK; DKB, AMK and SISO in experimental infections of E . coli GN 2411-5; S . marcescens T-55; P . aeruginosa KY-8510 harboring aminoglycoside inactivating enzyme AAC(6')-4, respectively. Steroids, 1983 Oct, 42(4), 389 - 99 Androstenedione metabolism in epithelial cells derived from early-lactation human milk; Perel E et al.; Epithelial cells derived from duct epithelium were cultured from early lactation human milk in medium supplemented with 15% fetal calf serum, insulin (0.3 u/ml), cortisol 21-sodium succinate (6 micrograms/ml) and amikacin (50 micrograms/ml) . The capacity of these cells to metabolize androstenedione to estrone, estradiol and C19 metabolites was studied during continuous culture . After extraction of the medium, the products were subjected to phenolic partition and separated by thin-layer and paper chromatography, followed by recrystallization to constant specific activity . The study demonstrated a progressive increase in the formation of estrone and testosterone over the first 24 h in culture, while estradiol formation showed an initial 2-4 h lag, then increased slowly . The C19 compounds identified were androsterone, 5 alpha-androstanedione, epiandrosterone, dihydrotestosterone and etiocholanolone . 5 alpha-Androstanedione and androsterone were the major 5 alpha-reduced metabolites . Since these cells are derived from normal duct epithelium, their metabolic characteristics may be more representative of normal breast tissue than those of tissue removed from patients with pathological breast disorders. Jpn J Antibiot, 1983 Oct, 36(10), 2813 - 9 {Clinical evaluation of ototoxicity associated with intravenous drip infusion of amikacin}; Maeyama T et al.; On the 53 patients with ENT (ears, nose, and throat) diseases, ototoxicity after intravenous drip infusion of amikacin (Biklin AMK) was studied . Each dose of AMK was 400 mg/day in adults and 4--8 mg/kg/day in children . From audiometric analysis, there were no patients with any hearing disturbances and subjective complaints concerning labyrinth injury . Also abnormal laboratory findings were not found in them . An intravenous drip infusion of AMK in adequate dosage would be beneficial to use against some infectious diseases of otorhinolaryngologic field. J Antimicrob Chemother, 1983 Oct, 12(4), 371 - 6 Reproducibility study of the pharmacokinetics of amikacin, gentamicin and tobramycin; a three-way crossover study; Dyas A et al.; The hypothesis that the pharmacokinetics of amikacin are more predictable than those of gentamicin or tobramycin was studied . In a three-way crossover design 58 volunteers received 7.5 mg/kg amikacin by iv infusion and either 1.5 mg/kg or 1 mg/kg gentamicin and tobramycin . The mean half-life and mean serum concentration at 1 h for each drug was determined . No consistent significant difference was found between the pharmacokinetics of amikacin and the other two drugs. Clin Pharmacokinet, 1983 Sep-Oct, 8(5), 456 - 62 Multiple-dose non-linear regression analysis program . Aminoglycoside dose prediction; Koup JR et al.; The ability of a new multiple-dose non-linear regression analysis program to predict steady-state aminoglycoside peak and trough serum concentrations was evaluated . 30 patients receiving either amikacin (7), gentamicin (10) or tobramycin (13) were studied . A standard method of prediction which requires the collection of 3 or 4 serum samples during a dosing interval and a predictive method which relies upon population-based estimates of pharmacokinetic parameters were compared with the new approach which requires the collection of 2 serum samples . There were no significant differences between the methods which utilised serum concentration data with regard to predictive precision (mean prediction error of about 10%) . These methods were more precise than the population-based method (p less than 0.01, mean prediction error 29.1%) . None of the methods produced biased estimates . These results indicate that when the regression program is employed, valid estimates of pharmacokinetic parameters and prediction of steady-state serum concentrations can be obtained with fewer serum samples than have been recommended. Clin Chem, 1983 Sep, 29(9), 1628 - 34 Automated fluorometer/photometer system for homogeneous immunoassays; Li TM et al.; A fully automated bench-top clinical analyzer (OPTIMATE TM; Ames/Gilford) performs homogeneous fluorescent immunoassays, colorimetric immunoassays, and determinations of routine blood analytes; drugs, enzymes, metabolites, specific proteins, and hormones in serum . Unique features include a combination fluorescence/absorbance aspirating thermocuvette, a photon-counting fluorometer/photometer, a multi-reagent distribution valve to dispense as many as three reagents plus buffer, and a user-replaceable programmable memory cartridge for software updates . We have evaluated the performance of OPTIMATE substrate-labeled fluorescent immunoassays for gentamicin, tobramycin, amikacin, theophylline, phenytoin, phenobarbital, primidone, carbamazepine, and quinidine with this automated system . A sample throughput of 92 samples per hour is achieved by reading fixed-point fluorescence results every 39 s after an initial 4-min reaction period . Precision studies indicate typical CVs of less than or equal to 6% for mid-range controls . Standard curves can be reused for as long as two weeks before recalibration . With clinical samples, results by the OPTIMATE procedure correlated well (r greater than or equal to 0.97) with those by a reference method. Ther Drug Monit, 1983 Jun, 5(2), 179 - 83 Monitoring of amikacin in the neonate; Rusconi F et al.; The purpose of this study was to analyze the role of gestational and postnatal age and of clinical conditions {e.g., respiratory distress syndrome (RDS)} on serum concentrations of amikacin in neonates treated according to commonly recommended dose schedules . Thirty-nine neonates (28.5-42 weeks of gestational age) were treated with the aminoglycoside at a mean dose of 7.2 mg/kg every 12 h for an average period of 6.5 days, and serum levels were monitored throughout treatment . Both gestational and postnatal age influenced amikacin levels . During the first days of life the presence of RDS was found to be strongly associated with amikacin accumulation . Neonates with retarded intrauterine growth according to their gestational age tended to have lower amikacin trough levels in the first days of life . No correlation was found between amikacin serum levels and hematocrit . Peak concentrations of the drug did not correlate with vital or clinical data, probably because of the variability in drug absorption from the intramuscular injection site . These data are discussed in light of the development of renal function and changes in body fluid compartments occurring in the preterm and term neonates during the first weeks of life. Antimicrob Agents Chemother, 1983 Jun, 23(6), 888 - 91 Increase of amikacin half-life during therapy in patients with renal insufficiency; Blaser J et al.; Serum kinetics of amikacin were investigated in 17 severely ill patients . During both the first and last dose intervals of therapy, the serum concentration time course of every patient was documented by 17 blood samples . Six of the patients had moderate to severe renal insufficiency (serum creatinine greater than 1.5 mg/100 ml) . In this group of patients, a pronounced rise in serum half-life of amikacin was observed, increasing from a mean of 11.2 to 21.5 h for the first and last interval, respectively . In contrast, mean half-life remained stable in the group of 11 patients with normal renal function . No change in mean serum creatinine occurred in either group, when data from the beginning and the end of therapy were compared . Therefore, the increase of amikacin half-life is apparently not due to a reduction of the glomerular filtration rate, but rather to a decrease of the ratio of amikacin to creatinine clearance . Indeed, a significant reduction of this ratio could be shown in the seven patients in which 24-h creatinine clearance was determined during the first and last day of therapy . This phenomenon is discussed in the context of aminoglycoside accumulation in deep compartments . We conclude that the daily dose of amikacin has to be reduced during therapy in patients with impaired, but stable, renal function. Tubercle, 1983 Jun, 64(2), 111 - 8 Amikacin in the treatment of pulmonary tuberculosis; Allen BW et al.; Sensitivity tests on strains from 11 patients with pulmonary tuberculosis, previously treated with kanamycin and/or capreomycin, showed incomplete cross-resistance between amikacin and capreomycin but complete cross-resistance between amikacin and kanamycin . Treatment with amikacin of 4 patients with multiply resistant strains resulted in no response as assessed by sputum smears and cultures, but resistance emerged to amikacin, kanamycin and capreomycin . Amikacin has no role in the treatment of tuberculosis as it cannot be given as an alternative to kanamycin, has no advantages over it and is more expensive. Br J Ophthalmol, 1983 May, 67(5), 324 - 6 Mycobacterium chelonei keratitis: a case report; Mirate DJ et al.; The case is reported of a patient who initially presented with a dendritiform corneal ulcer that ultimately failed to heal and in which Mycobacterium chelonei was repeatedly cultured . The organism was sensitive only to kanamycin and amikacin; however, topical administration of these antibiotics failed to achieve a complete cure . Penetrating keratoplasty was ultimately required to eradicate the organism from the cornea. Arch Otorhinolaryngol, 1983 Apr, 237(3), 201 - 8 Degeneration of cochlear neurons after amikacin intoxication in the rat; Bichler E et al.; Intoxication with high doses of the aminoglycoside antibiotic amikacin in a supranormal sensitive period in the rat induces complete destruction of the inner and outer hair cells in the organ of Corti in all turns, whereas the supporting cells remain partially preserved in the upper turns . With increasing survival time, the number of ganglion cells in the spiral ganglion decreases progressively, reaching a minimum of about 10% surviving cells after 12 months . Both type I and type II neurons are subject to retrograde degeneration, although type-II cells degenerate more slowly than type-I cells . The presence or absence of supporting cells in the organ of Corti does not seem to influence neuronal degeneration . This retrograde degeneration is similar in all animals so far studied but its time course is different from different species . Retrograde degeneration after destruction of Corti's organ is a long-lasting process and is never completed at once . This must be taken into consideration in the treatment of total deafness with electric stimulation of surviving neurons. Int J Clin Pharmacol Ther Toxicol, 1983 Apr, 21(4), 197 - 202 Influence of type of dialyzer on the pharmacokinetics of amikacin; Lanao JM et al.; The pharmacokinetics of amikacin was studied in 18 patients with terminal renal impairment (Clcr less than 5 ml/min during the course of 4-5 h hemodialysis sessions using four different kinds of dialyzer: RP 6, RP 514, Dialix, and Ultra Flo II . All patients received a single dose of 7.5 mg amikacin/kg body wt . at the beginning of the dialysis session . The type of dialyzers influences the serum half-life, the extraction coefficient, and the percentage of dose extracted during dialysis . A linear relationship was established between the percentage of the dose extracted by dialysis and the dialysis clearance of the antibiotic. Eur J Pediatr, 1983 Apr, 140(2), 135 - 7 Abdominal nocardiosis in a Sudanese girl; Salfield SA et al.; A Sudanese girl became desperately ill with liver and kidney abscesses due to Nocardia asteroides . She did not have pulmonary or cutaneous infection . She recovered after surgical drainage of the abscesses and prolonged treatment with intravenous amikacin and high dosage cotrimoxazole and sulphadimidine . After recovery normal neutrophil function, cell-mediated and humoral immunity were demonstrated. An Esp Pediatr, 1983 Mar, 18(3), 217 - 23 {In vitro study of the stability of reduced intraerythrocyte glutathione against a group of drugs frequently used during the neonatal period}; Sanchez Artiles J et al.; Authors have studied in 32 samples of cord blood (normal newborns and normal births) the stability of glutathione reduced form (GSH) in human erythrocytes opposite to ten drugs (gentamicin, cephazolin, amikacin, carbenicillin, amoxicillin, benzodiacepine, metil-prednisolone, phenilbarbituric acid, fosfomycin, trimethroprim-sulphamethoxazole) using it at similar concentration to the highest haemotic levels that are obtained in the newborn with therapeutic doses . They showed that these drugs have not an effect on stability of GSH . For this reason is very unprobable that these drugs are cause of haemolitic crisis in the newborn . In the another hand, they suggest the use co-trimoxazole in the newborn always, in correct doses. Jpn J Antibiot, 1983 Mar, 36(3), 522 - 8 {Intrathecal administration of amikacin in postoperative refractory meningitis}; Yamashima T et al.; The intrathecal administration of amikacin (AMK) (50--100 mg/day) was effective for 3 cases of postoperative refractory meningitis caused by gentamicin (GM) resistant organisms . The infecting pathogen of case 1 was K . pneumoniae and that of case 2 was S . epidermidis, while no pathogen was cultured in case 3 . The causative pathogens in the former were eradicated only with AMK . No therapeutic response was gained with GM, but with AMK in the latter . High tone hearing impairment was observed in case 1 and transient vomiting was observed in case 3 . However, these side effects were trivial for the severity of disease . It is suggested in these 3 cases that the high dose intrathecal administration of AMK may be extremely useful in the treatment of postoperative refractory meningitis which has shown no response to GM. Antimicrob Agents Chemother, 1983 Jan, 23(1), 133 - 7 Effect of furosemide on aminoglycoside-induced nephrotoxicity and auditory toxicity in humans; Smith CR et al.; We analyzed data from three prospective, controlled, randomized, double-blind clinical trails to determine whether furosemide increases the nephrotoxicity and auditory toxicity of aminoglycosides . All patients who received at least 72 h of treatment and who had no other cause for nephrotoxicity or auditory toxicity were included in the analysis . Nephrotoxicity developed in 10 of 50 (20.0%) patients given furosemide and in 38 of 222 (17.1%) patients not given furosemide (P greater than 0.3) . Auditory toxicity developed in 5 of 23 patients (21.7%) given furosemide and in 28 of 119 patients (23.5%) not given furosemide (P greater than 0.3) . In each case, the groups receiving and not receiving furosemide did not differ in mean age, initial creatinine, duration of aminoglycoside therapy, mean change in auditory acuity or creatinine, mean number of days to the development of toxicity, the frequency with which gentamicin, tobramycin, amikacin, or cephalothin was administered, or the mean predose and 1-h postdose plasma aminoglycoside levels . We conclude that furosemide use should not be considered a major risk factor for the development of aminoglycoside-induced nephrotoxicity or auditory toxicity. Drug Intell Clin Pharm, 1983 Jan, 17(1), 33 - 8 Aminoglycoside pharmacokinetics on a microcomputer; Kaka JS et al.; The authors describe the use of a microcomputer to evaluate an existing dosage regimen and to determine a new regimen and steady-state peak and trough levels for four aminoglycoside antibiotics--amikacin, gentamicin, kanamycin, and tobramycin . The microcomputer program is based on a one-compartment open pharmacokinetic model for the aminoglycosides . It accounts for patients' sex, age, height, obesity, and ascitic compartment . The program is divided into seven subprograms for each of the four aminoglycosides: (1) steady-state peak and trough levels are predicted, based on serum creatinine for a given dosage regimen; (2) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained, based on serum creatinine; (3) a dosage regimen is determined, on the basis of serum creatinine, for desired steady-state peak and trough levels; (4) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained for given aminoglycoside serum levels; (5) a dosage regimen for desired peak and trough levels is ascertained for given aminoglycoside serum levels; (6) a dosage regimen that conforms to 6, 8, 12, 16, or 24 hours is ascertained from data collected using Sawchuk's and Zaske's method; and (7) a dosage regimen, estimated for desired peak and trough levels, is estimated from data collected using Sawchuk's and Zaske's method. Arzneimittelforschung, 1983, 33(11), 1607 - 8 Amikacin levels in human aqueous humor; Radda TM et al.; Amikacin is one of the newer aminoglycoside antibiotics . The penetration of amikacin into the human primary aqueous humor after intramuscular application was investigated . Comparing our results with reports concerning the blood aqueous permeability of gentamicin and tobramycin we could not find any significantly better penetration of amikacin into the human aqueous humor after i.m . injection . The advantage of amikacin lies in its effectiveness against bacteria resistant to other aminoglycosides. Jpn J Antibiot, 1982 Dec, 35(12), 2785 - 96 {Clinical use of amikacin sulfate in the treatment of bacterial infections and prevention of postoperative infections in the orthopedic field}; Ono K et al.; Investigation was made on the effectiveness and safety of amikacin (AMK) in the treatment of bacterial infections and prevention of postoperative infections in the orthopedic field . The details of 14 infectious patients treated with AMK were as follows; osteomyelitis in 5, purulent arthritis in 3, decubitius in 3, cystitis in 2 and purulent peritonitis in 1 . For prevention of postoperative infections, AMK was administered to 9 patients . In 14 infectious patients, clinical response was excellent in 2, good in 11 and poor in 1, while in 9 postoperative patients clinical response was excellent or good in all of them . As side effects, a slight rise of the GOT and GPT levels was observed in 1 but normalized by discontinuation of the medication . In the aspects of effectiveness and safety, AMK may be considered to be a useful available antibiotic in the orthopedic field. Biochem Pharmacol, 1982 Dec 1, 31(23), 3861 - 70 Mechanism of aminoglycoside-induced lysosomal phospholipidosis: in vitro and in vivo studies with gentamicin and amikacin; Laurent G et al.; Gentamicin, a widely used aminoglycoside antibiotic, is concentrated in lysosomes of proximal tubular cells of the kidney, and induces therein an accumulation of myelin-like material . We show that treatment of rats with Gentamicin (10 mg/kg, 7 days) induces a loss of activity of lysosomal sphingomyelinase and phospholipase A1, associated with an increase in the amount of total lipid phosphorus in the kidney cortex . In vitro, Gentamicin is shown by gel permeation to bind to phospholipid bilayers (liposomes) under conditions which mimic the lysosomal environment (acid pH and presence of phosphatidylinositol) . The reversal of this binding by an increase in the ionic strength (less than 0.04) suggests electrostatic interaction between the hydrophilic, polycationic aminoglycoside and the negatively charged phospholipids . Binding of Gentamicin impairs the hydrolysis of phosphatidylcholine present in the bilayer, by lysosomal phospholipases A1 and A2 from the liver or kidney . We also show that lysosomal sphingomyelinase is readily and irreversibly inactivated by liposomes in the absence of detergent . The lysosomal phospholipidosis induced by Gentamicin in the kidney, as in cultured cells {Aubert-Tulkens et al., Lab . Invest . 40, 481 (1979)} appears therefore to be a direct consequence of the lysosomotropic character of this drug and its ability to inhibit therein phospholipid breakdown . Amikacin, a semi-synthetic aminoglycoside, binds more loosely to phospholipid bilayers, induces less inhibition of phospholipases in vitro and is less taken up by tubular cells in vivo . Accordingly, Amikacin does not provoke significant lysosomal phospholipidosis or loss of sphingomyelinase and phospholipase A1 activities in vivo at the doses and time investigated (0-40 mg/kg, 7 days) . Inasmuch as Amikacin is reported to be less toxic to the kidney, we suggest that lysosomal alterations are an early and significant step in aminoglycoside-induced nephrotoxicity. Nouv Presse Med, 1982 Nov 18, 11(46), 3451 - 5 {Dibekacin: diffusion in bronchial mucus}; Morel C et al.; The study of the bronchial concentration of dibekacin has shown a different degree of activity than that of gentamicin . This activity resembles that of amikacin with a three hour time lag from the appearance of the bronchial peak in relationship to the serum peak . In addition there seems to be a special passage mechanism for the antibiotic from the blood into the bronchial secretions since we observed an increase in the mucus/serum ratio through time. Nouv Presse Med, 1982 Nov 18, 11(46), 3419 - 25 {Functional, histological, biochemical renal modifications . Comparative study of dibekacin, gentamicin, tobramycin, netilmicin and amikacin}; Viotte G et al.; In this study, we evaluate the nephrotoxic potential of dibekacin (D) compared to gentamicin (G), tobramycin (T), amikacin (A) and netilmicin (N) . The mean features of aminoglycoside nephrotoxicity are: a lysosomal membrane fragilization, a lysosomal phospholipidosis characterized by a decrease activity of sphingomyelinase, an increase lysosomal volume with both an increase of individual size and an increase number of lysosomes, a cell necrosis and renal failure . We have quantified these parameters biochemically and morphometrically . We can classify, considering doses and durations, the aminoglycosides as gentamicin greater than or equal to netilmicin greater than dibekacin = tobramycin greater than amikacin for decreasing nephrotoxic incidence. Clin Pharm, 1982 Nov-Dec, 1(6), 539 - 43 Ototoxicity and pharmacokinetically determined dosages of amikacin in granulocytopenic cancer patients; Danhauer FJ et al.; Pharmacokinetic principles were used to determine amikacin doses for granulocytopenic cancer patients on empirical antibiotic regimens, and audiometry was used to determine the effect of this treatment on auditory acuity . Patients received ticarcillin 300 mg/kg/day plus amikacin, or moxalactam 8 g/day plus amikacin, in a blinded study . Amikacin doses were calculated to achieve a peak serum concentration (one hour after infusion) of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml . Baseline audiometry was conducted, and follow-up audiometry was done on completion of the antibiotic therapy . A decrease of greater than or equal to 20 db at any frequency in one or both ears was considered indicative of ototoxicity . Of 201 patients on the empirical antibiotic protocol, 55 had courses of treatment that could be evaluated . Ototoxicity not attributable to any other drug or disease process occurred in 10 patients . There were no significant differences related to age, weight, daily dose, or total dose between patients who developed ototoxicity and those who did not . Peak and trough amikacin concentrations were not significantly different between groups . More women than men developed ototoxicity . Duration of therapy for the ototoxic group was longer, and there was a trend for those with abnormal initial audiograms to develop further evidence of impairment . The significant risk factor for auditory toxicity was the combination of duration of aminoglycoside therapy and total dose per kilogram . Pharmacokinetically calculated doses of amikacin did not result in a higher incidence of auditory toxicity than reported in previous studies. Acta Otolaryngol, 1982 Nov-Dec, 94(5-6), 431 - 8 Spiral ganglion changes after massive aminoglycoside treatment in the guinea pig . Counts and ultrastructure; Koitchev K et al.; Morphological changes of the eighth nerve were observed in the guinea pig between 1 month and 1 year after treatment with large doses of the antibiotic amikacin which resulted in complete cochlear hair cell destruction . The neural retrograde degeneration was found to be relatively fast, with a considerable loss (30 to 55%) of ganglion cells one month after treatment, continuously increasing (up to 85) after one year . Gross changes in the habenula perforata and in the spiral ganglion are described, together with ultrastructural alterations of organelles important for the cell metabolism and axonal transport . The rapid degeneration and the morphological findings suggest a direct influence of toxic substances on the ganglion cells. Antimicrob Agents Chemother, 1982 Sep, 22(3), 376 - 9 Inactivation of amikacin and gentamicin by carbenicillin in patients with end-stage renal failure; Blair DC et al.; Aminoglycosides are inactivated by carbenicillin in vitro and in patients with end-stage renal failure . In vitro, amikacin is inactivated to a lesser extent than is gentamicin . In five patients on chronic hemodialysis, serum levels of amikacin alone and after repeated intravenous carbenicillin infusions were determined . Analogous gentamicin studies were conducted with five different patients . Neither amikacin serum levels nor serum clearances were affected by carbenicillin . The mean gentamicin serum half-life was significantly lower in the presence of carbenicillin: 18.4 +/- 8.2 compared with 61.6 +/- 30.7 h . Serum clearance increased significantly . The inactivation of gentamicin by carbenicillin was both time related (greater than 12 h of exposure) and concentration dependent (molar carbenicillin/gentamicin ratios greater than or equal to 39:1) . Amikacin would be preferable to gentamicin in patients with end-stage renal failure. J Chromatogr, 1982 Aug 13, 231(1), 145 - 54 Determination of amikacin in microlitre quantities of biological fluids by high-performance liquid chromatography using 1-fluoro-2,4-dinitrobenzene derivatization; Wong LT et al.; Pre-column derivatization of amikacin with 1-fluoro-2,4-dinitrobenzene in 25 microliter of guinea pig plasma or human serum produced a stable chromophore which was measured by UV detection after rapid separation on normal-phase or reversed-phase high-performance liquid chromatography systems . The reversed-phase system, selected for routine analysis due to instability of the normal-phase column, consisted of an Ultrasphere-ODS C18 column preceded by a guard column, and used acetonitrile--water (68:32) as the mobile phase . A high degree of linearity was found in the range of 2-64 microgram/ml with a coefficient of variation averaging less than 5%. Dtsch Med Wochenschr, 1982 Aug 6, 107(31-32), 1182 - 4 {Control of serum levels of tobramycin and amikacin during clinical routine treatment conditions (author's transl)}; Stark GB et al.; 576 serum levels at peak and before the next dosage (end level) were determined during clinical treatment conditions using radioimmunoassay in 131 patients treated with tobramycin or amikacin because of life-threatening infections . Only 42.8% of tobramycin serum peak levels were within the therapeutic range . 3.6% were potentially toxic, however, 53.6% were in a subtherapeutic range . After amikacin administration only 25% of serum peak levels were in a subtherapeutic range . 54.2% were therapeutic and 20.8% were potentially toxic . The main reason for increased peak and end serum levels was diminished renal function . Infusion treatment with more than 3 1/24 hrs lowered serum peak levels of tobramycin by 38% and of amikacin by 31% . Single doses of 80 mg of tobramycin lead to subtherapeutic concentrations too frequently, whereas single doses of 500 mg of amikacin too frequently lead to potentially toxic serum levels . Control of serum levels during aminoglycoside treatment is recommended particularly in patients at risk with life-threatening infections. Jpn J Antibiot, 1982 Aug, 35(8), 2111 - 25 {Experimental and clinical studies of intravenous infusion of amikacin in acute respiratory tract infections}; Ito T; Pharmacokinetic and clinical studies on amikacin (AMK) by intravenous drip (i.v.d.) infusion were performed, and the following results were obtained . 1 . Serum concentrations of AMK were determined in 4 patients with normal renal function after 1 hour i.v.d . infusion of 200 mg of AMK . The mean peak serum concentration was 14.20 +/- 0.88 micrograms/ml at the termination of i.v.d . infusion and declined to 2.30 +/- 0.79 micrograms/ml at 4 hours later . The half-life was 1.55 +/- 0.28 hours . 2 . Twenty-three patients with severe pulmonary infection received 1 hour i.v.d . infusion of 200 mg of AMK 2 to 3 times a day . Clinical response was good in 17 cases, fair in 4 and poor in 2 . Thus, 73.9% of the patients responded to AMK . 3 . No adverse effects were observed with the exception of tinnitus and hearing loss in 1 case . Therefore, it is thought that the i.v.d . infusion of AMK will be useful for treatment of severe infectious patients with bleeding tendency and emaciation. Jpn J Antibiot, 1982 Aug, 35(8), 2100 - 10 {Effects of intravenous infusion of amikacin . Intraperitoneal administration to rats before and in the early stage of pregnancy . Segment 1}; Akutsu S et al.; Fertility study on amikacin sulfate (AMK) was carried out in Wistar rats . AMK was administered intraperitoneally at the doses of 0, 25, 100 mg/kg/day and 200 mg/kg/day in males for 60 days prior to mating and mating period and in females for 14 days prior to mating, mating period and day 0-7 of gestation . The drug induced no significant changes or signs in parent animals, except that soft feces was occasionally found at the 100 mg/kg/day and 200 mg/kg/day and the impairment in kidneys was recognized only at the 200 mg/kg/day . There were no adverse effects on mating, fertility or reproduction indices in males and females . And there were no evidences of teratogenic or embryotoxic effects in at any doses of AMK. Jpn J Antibiot, 1982 Aug, 35(8), 2069 - 99 {Toxicological study of amikacin following intravenous drip infusion . 2 . Subacute toxicity in dogs after intravenous injection}; Akutsu S et al.; Subacute toxicity of amikacin sulfate (AMK) was investigated with 50 Beagle dogs (male 25, female 25) . As a substitute for drip intravenous infusion (d.i.v.), AMK was administered by intravenous injection (i.v.) twice a day, 1 hour apart, for 38 days at daily doses of 400, 200, 100 mg/kg and 25 mg/kg . 1 . At the doses of 25 mg/kg and 100 mg/kg, there were no significant changes or signs recognized as toxicological effects of AMK . 2 . At the dose of 200 mg/kg, slight renal damages were observed in 3 of 5 males and 2 of 5 females . These were slight elevation of urea N and creatinine, and slight degeneration or regeneration of the renal proximal tubules . 3 . At the dose of 400 mg/kg, renal damages were noted in all the dogs . Two males and 1 female died after 14-17 days' treatment and the remainders were sacrificed for inspection after 18-20 days' treatment . In any dogs, the adverse findings were mainly observed in the renal proximal tubules but not in the glomeruli . In the other organs, there were no significant impairments . 4 . From these results, it is considered that the maximum no effect dose of AMK is 100 mg/kg. Jpn J Antibiot, 1982 Aug, 35(8), 2048 - 67 {Toxicological study of amikacin following intravenous drip infusion . 1 . Acute toxicity in rats, rabbits and dogs, and subacute toxicity in rabbits}; Nakamura K et al.; Acute toxicity of amikacin sulfate (AMK) was studied in rats, rabbits and dogs following 1 hour drip intravenous infusion (1 hour d.i.v.), and compared with those after intravenous injection (i.v.) . Subacute toxicity was studied in rabbits following 1 hour d.i.v . of AMK at doses of 400, 200, 100 and 25 mg/kg for 36 days . Acute toxicity: Acute toxicity of AMK by 1 hour d.i.v . was extremely diminished as compared with that by i.v . judging from LD50, the toxicity was approximately 1/6 in rats and approximately 1/2 in rabbits and dogs . No difference was observed between males and females . Subacute toxicity: 1 . No death was found in all rabbits . 2 . At the doses of 25 mg/kg and 100 mg/kg, there were no significant changes or signs recognized as toxicological effects of AMK . 3 . At the dose of 200 mg/kg, very slight renal damages were observed histopathologically in all the 5 rabbits . 4 . At the dose of 400 mg/kg, slight or moderate renal damages were observed in all the rabbits . Those were mainly dilatation of renal proximal tubules, hydropic swelling and degeneration of renal proximal tubular epithelium . No significant impairment effect of AMK was found in heart, lung, liver and other organs . 5 . From these results, it is considered that the maximum no effect dose from a view point of safety is about 100 mg/kg in this study. J Clin Pharmacol, 1982 Aug-Sep, 22(8-9), 403 - 9 Pharmacokinetics of amikacin and cephalothin in bedridden elderly patients; Yasuhara H et al.; The pharmacokinetics of amikacin (5.5 mg/kg intramuscularly) and cephalothin (1000 mg/body intravenously) in bedridden elderly patients were studied in comparison with those in healthy volunteers . The eliminations of amikacin and cephalothin from the plasma followed the course of a one-compartment open model . For amikacin, five healthy volunteers, elimination rate constant Kel was 0.396 hr-1, biologic half-life t1/2 was 1.80 hour, volume of distribution Vd was 0.201 l./kg; in five bedridden elderly patients, Kel was 0.208 hr-1, t1/2 was 3.55 hours, Vd was 0.376 l./kg . Cumulative renal excretion of amikacin in 8 hours was 44 per cent of the total dose in bedridden elderly patients and 69 per cent in healthy volunteers . For cephalothin, in seven healthy volunteers, Kel was 0.0353 min-1, t1/2 was 19.7 min, Vd was 0.176 l./kg; in four bedridden elderly patients, Kel was 0.0127 min-1, t1/2 was 56.4 min, Vd was 0.283 l./kg . Cumulative renal excretion of cephalothin reached a plateau by 4 hours of 40.8 per cent of the total dose in bedridden elderly patients and of 56.7 per cent in healthy volunteers . These results suggest that in bedridden elderly patients decreased renal excretion of amikacin and cephalothin is related to decreased renal function and an increased Vd. Antimicrob Agents Chemother, 1982 Aug, 22(2), 231 - 6 Ribosomal resistance in the gentamicin producer organism Micromonospora purpurea; Piendl W et al.; The mechanism of resistance of the gentamicin-producing organism Micromonospora purpurea was analyzed . Determination of minimal inhibitory concentrations revealed high resistance to the 4,6-substituted deoxystreptamine aminoglycosides amikacin, gentamicin, kanamycin, netilmicin, sisomicin, and tobramycin and also to lividomycin A and hygromycin B, but susceptibility to streptomycin, dihydrostreptomycin, paromomycin, and neomycin during all phases of the growth cycle . The nonproducing, closely related Micromonospora melanosporea was susceptible to these compounds . In agreement with results from previous studies (R . Benveniste and J . Davies, Proc . Natl . Acad . Sci . U.S.A . 70:2276-2280, 1973), extracts from M . purpurea showed no activity of enzymes specifically modifying gentamicin . 70S ribosomes from M . purpurea but not from M . melanosporea were resistant to inhibition by gentamicin, kanamycin, tobramycin, and lividomycin in a polyuridylic acid-dependent polyphenylalanine synthesis system and susceptible to those compounds which were inhibitory in vivo . The former antibiotics were also unable to induce misreading . Subunit exchange experiments between M . purpurea and M . melanosporea showed that the main site for inhibition and induction of misreading is the 30S subunit (up to gentamicin concentrations of 10 micrograms/ml). Antimicrob Agents Chemother, 1982 Aug, 22(2), 193 - 7 Comparison of standard versus pharmacokinetically adjusted amikacin dosing in granulocytopenic cancer patients; Finley RS et al.; The capabilities of two pharmacokinetic amikacin dosing methods were evaluated and compared with the standard amikacin dosage recommended by the manufacturer . Study patients participated in two consecutive prospective randomized double-blind trials of empiric antibiotic therapy for febrile episodes during granulocytopenia . Patients in study 1 received amikacin at a dosage of 15 mg/kg per day in four divided doses in combination with either ticarcillin or piperacillin . Patients in study 2 received either ticarcillin or moxalactam in combination with amikacin . Amikacin dosages in study 2 were adjusted to achieve a 1-h-postinfusion concentration of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml . Initial amikacin dosage requirements were established based on the lean body weight and estimated renal function of the patient . If amikacin serum concentrations were not within acceptable ranges, further dosage adjustments were made by using patient-specific pharmacokinetic parameters . The median 1-h-postinfusion concentration of amikacin in study 1 was 13.0 micrograms/ml, with a median trough concentration of 6.1 micrograms/ml . In study 2 the median 1-h-postinfusion concentration was 20.8 micrograms/ml, with a median trough of 6.4 micrograms/ml . Patients in study 2 required a mean dosage of 29.4 mg/kg per day . The incidence of amikacin-induced nephrotoxicity was not increased despite the substantial increase in dosage . Ototoxicity was not evaluated in study 1, but the incidence of ototoxicity in study 2 (17%) exceeded the incidence observed in a previous amikacin-plus-ticarcillin trial in which patients received 15 mg of amikacin per kg per day. Antimicrob Agents Chemother, 1982 Jul, 22(1), 78 - 82 Decreased susceptibility to 4'-deoxy-6'-N-methylamikacin (BB-K311) conferred by a mutant plasmid in Escherichia coli; Perlin MH et al.; Escherichia coli MP6 contains a plasmid that encodes aminoglycoside 3'-phosphotransferase II, which phosphorylates kanamycin and confers high-level kanamycin resistance, Amikacin is a minor substrate of this enzyme, but MP6 is susceptible to amikacin . Strain MP10 has a spontaneous mutation in the plasmid of MP6 that increases the aminoglycoside 3'-phosphotransferase II activity not only against kanamycin but also against amikacin . This mutation is also responsible for the appearance of resistance to amikacin in MP10 . Resistance to 4'-deoxy-6'-N-methylamikacin (BB-K311) by enzymatic modification has not been reported previously . As with amikacin, MP6 was susceptible to BB-K311 and its aminoglycoside 3'-phosphotransferase II did not phosphorylate this amikacin derivative appreciably . We found that the plasmid-borne mutation in MP10, however, localized by being cloned with a 3.7-megadalton HindIII fragment containing the aminoglycoside 3'-phosphotransferase II gene, resulted in increased phosphorylation of BB-K311 and resistance to it . Thus, the mutation distinguishing MP6 and MP10 has increased the activity of an existing aminoglycoside-modifying enzyme and produced new bacterial resistance to two previously minor substrates of the enzyme. Jpn J Antibiot, 1982 Jun, 35(6), 1374 - 8 {Experimental and clinical studies of fortimicin in the field of dermatology}; Suwaki M et al.; 1 . Fortimicin (KW-1070) was found to be similar to amikacin in vitro activity against S . aureus of 27 strains and S . epidermidis of 17 strains isolated in dermatological field . 2 . Serum and skin levels of the drug were determined in rats . Mean serum levels (n = 4) were 4.91 mcg/ml at 1/4 hour, 2.40 mcg/ml at 1/2 hour, 2.40 mcg/ml at 1 hour and 0.51 mcg/ml at 2 hours . The corresponding skin levels were 2.15 mcg/g, 2.27 mcg/g, 0.83 mcg/g and 0.19 mcg/g . 3 . Seven cases with dermatological infections were treated with fortimicin . No side effects were observed both in subjective and in laboratory findings. J Anim Sci, 1982 Jun, 54(6), 1105 - 10 Effects of amikacin sulfate on the motility of stallion and bull spermatozoa at different temperatures and intervals of storage; Arriola J et al.; Because microfloral content of stallion semen tends to be high, and strains may be resistant to commonly used antibiotics, amikacin was tested with stallion semen and compared with bull semen . Nine ejaculates to stallion semen were incubated at 37 C in egg yolk-tris extender for 0, 2, 4, 6, 8 and 10 h in the presence of amikacin concentrations of 0, 50, 100, 250, 500, 1,000 and 10,000 microgram/ml, with penicillin and penicillin-streptomycin as controls . Averaged over all incubations, spermatozoal motility was 44, 48, 49, 46, 45, 45 and 19%, for increasing concentrations of amikacin, compared with 52 and 47% for penicillin and penicillin-streptomycin controls . The 10,000 microgram/ml concentration of amikacin was the only treatment that suppressed sperm motility (P less than .01) . Amikacin (0, 50, 100, 250, 500, 1,000 2,500, 5,000 and 10,000 microgram/ml) and 1,000 IU of penicillin G plus 1,000 microgram of streptomycin/ml or 10,000 IU of penicillin G/ml were added to nine ejaculates of bull semen stored at 4 C in egg yolk-tris extender, and evaluated after 0, 1, 3, 5 and 7 d . The percentage of motile spermatozoa, with increasing levels of amikacin, was 66, 67, 66, 64, 67, 68, 74, 68 and 53%, respectively . Amikacin, at 2,500 microgram/ml, resulted in the highest (P less than .01) motility compared to the other levels of antibiotics after 7 d storage . Both 10,000 microgram of amikacin and 10,000 IU of penicillin G/ml depressed (P less than .01) the mean percentage of motile bull spermatozoa . These studies demonstrate that high concentrations of amikacin can be added to stallion and bull semen without depressing motility of spermatozoa. Int J Clin Pharmacol Ther Toxicol, 1982 Jun, 20(6), 271 - 5 Disposition kinetics of amikacin in patients with renal impairment after intramuscular administration; Lanao JM et al.; The disposition kinetics of amikacin were established in 12 patients with varying degrees of renal impairment (Clcr less than 70 ml/min) after i.m . administration of a dose of 7.5 mg antibiotic/kg body wt . Administered intramuscularly, amikacin follows a single-compartment open kinetic model . A decrease may be observed in the absorption and elimination processes in this kind of patient, and mathematical relationships may be established between the variation in the pharmacokinetic parameters and the creatinine clearance . The decrease observed in the elimination constant of amikacin is similar to that observed after i.v . administration of the antibiotic . A dosage regimen for administration of the antibiotic is proposed for this kind of patient on the basis of desired peak and trough serum levels obtained throughout treatment. Clin Chem, 1982 Jun, 28(6), 1370 - 4 Homogeneous enzyme immunoassay for tobramycin evaluated and compared with a radioimmunoassay; Woo J et al.; We evaluated a commercially available homogeneous enzyme immunoassay (EMIT, Syva Co.) for tobramycin against a reference radioimmunoassay (RIA) method . Between-assay precision (CV) was 2.9% at 6.2 mg/L and 3.0% for values in the range of 1.0-7.6 mg/L . Accuracy based on a recovery experiment (1.0-13.0 mg/L) yielded an analytical recovery of 88-112% . A correlation study with 75 sera from patients on tobramycin therapy showed that EMIT = 0.984 RIA - 0.0808, r = 0.993 . Neither the EMIT nor the RIA procedure was affected by the presence of gentamicin, amikacin, and vancomycin . Absorbance data from the EMIT system calculated with the conventional RIA logit-log algorithm correlate well with results generated by the Syva data-handling system (logit-log = 1.077 Syva - 0.318, r = 0.998) . A reagent stability study indicated that the EMIT reagents, once reconstituted, remain stable for at least 17 days when stored at refrigerated temperatures, or 11 days if stored at room temperature, thus enabling frequent "stat" assays without the need to prepare a calibration curve each time. Jpn J Antibiot, 1982 May, 35(5), 1249 - 53 {Experiences with intravenous drip infusion therapy of amikacin for severe infections in patients of hematological disorder}; Hanada S et al.; Amikacin was studied for clinical effect in 7 patients with acute leukemia, 1 patient with chronic myelogenous leukemia-blastic crisis, 1 patient with malignant lymphoma and 1 patient with aplastic anemia, who were suffered from severe infection such as sepsis, pneumonia or subcutaneous abscess . Most of these patients had bleeding tendency, so amikacin was administered by intravenous drip infusion in a dose of 200 mg--400 mg for 1 hour . Total doses of amikacin were between 3.2 g and 12.6 g . These doses of amikacin gave good response to 3 patients with sepsis, 1 patient with subcutaneous abscess and 1 patient with pneumonia . We didn't observe any side effect most likely associated with amikacin . Therefore, intravenous drip administration of amikacin might be useful drug for management of severe infections in patients of hematological disorder, and seemed to be as safe as intramuscular administration. Ann Microbiol (Paris), 1982 May-Jun, 133(3), 409 - 16 {Comparison of light-scattering index 50% (LSI50) and inhibitory concentration 50% (CI50) (author's transl)}; Chung SS et al.; The "Autobac" apparatus permitted the rapid determination of the light-scattering index 50% (LSI50) and inhibitory concentration 50% (CI50) of eight antibiotics -- kanamycin, amikacin, lividomycin, gentamicin, tobramycin, sisomicin, netilmicin and colistin -- for the strain of Escherichia coli ATCC-25922 . The results were compared with those of the reference method using an agar dilution method . The percentage of inhibition (% I) was obtained from LSI by applying the formula % I = 10(-(GIXLSI)) . The growth index (GI) has an influence on the values of the rapid method . The best results were observed in the GI ranges of 1.2 to 1.7 . For all the antibiotics except tobramycin and colistin, the CI50 values of the two methods were very similar . The values of LSI50 were not assimiliated to those of CI50 . These three parameters had a small variability . The averages of standard deviation were 0.23 log2 for the CI50 of the reference method, 0.24 log2 for the CI50 of the rapid method and 0.32 log2 for the LSI50 . The "Autobac" enables the determination of CI50 by a simpler and faster technique. Immun Infekt, 1982 Mar, 10(2), 76 - 81 {CSF levels of amikacin following systemic application in patients with slightly and severely impaired blood cerebrospinal barrier (author's transl)}; Bruckner O et al.; Levels of amikacin after systemic application of 350 mg were determined by the agar well diffusion method in 12 samples of CSF and serum of 7 patients with bacterial meningitis and in 2 samples of 2 patients with viral meningitis . Only in 2 samples of CSF drawn after the first systemic application of 350 mg i.m . no antibiotic activity was detectable . In 7 specimens of CSF levels of amikacin were greater than or equal to 3 microgram/ml . In 12 tests of CSF of neurosurgical patients with only slight impairment of the blood-CSF-barrier, taken for comparison reasons, only in 6 samples antibiotic activity was found . Only one test revealed CSF-concentration of amikacin higher then 3 microgram/ml. Am J Dis Child, 1982 Mar, 136(3), 223 - 5 Renal and Auditory toxic effects of amikacin in children with cancer; Faden H et al.; Amikacin sulfate was given to 21 febrile children with neutropenia and cancer for 9 +/- 3 days . Peak serum amikacin levels ranged between 13 and 32 microgram/mL, and trough levels were consistently less than 2 microgram/mL . Renal toxic effects were detected in two children (9.5%) and were extremely mild . Two additional children (16.5%) experienced mild, transient, unilateral, high-frequency hearing losses . The lack of serious renal and auditory impairment suggests that children are at less risk than adults from aminoglycoside therapy. Ann Surg, 1982 Mar, 195(3), 287 - 93 Aminoglycoside dosing in renal transplant patients . Comparison of nomogram and individualized pharmacokinetic methods in patients with shifting renal function; Tofte RW et al.; Serum amikacin concentrations were compared in infected renal transplant recipients that were compared in infected renal transplant recipients that were dosed using a creatinine-based nomogram (group I) or an individual computer-assisted pharmacokinetic dosing method (group II) . A total of 30 treatment courses were administered . Mean postinfusion peak levels were 22 microgram/ml in group I and 23.4 microgram/ml in group II . Mean serum trough levels were 8.8 microgram/ml and 5.5 microgram/ml in groups I and II, respectively . Both peak and trough serum levels were significantly more often in the acceptable therapeutic (peak 20-32 microgram/ml) and nontoxic (through less than 10 microgram/ml) ranges in group 11 patients . Seventy-seven per cent of group II and 38% of group I peak levels were in the therapeutic range, while 87% of group II and 70% of group I trough levels were less than 10 microgram/ml . Ototoxicity developed with similar frequency in both groups and occurred significantly more often with a peak level greater than 32 microgram/ml . Declining renal function, usually as a result of allograft rejection, occurred in seven (44%) group I and only three (25%) group II patients but could not be exclusively related to amikacin in any patient . A serum trough level of greater than 10 microgram/ml was associated with an increased risk of declining renal function independent of other risk factors . Failures of aminoglycoside therapy are frequently associated with inadequate serum levels . Conversely, ototoxicity and nephrotoxicity may be related to elevated serum aminoglycoside concentrations . For these reasons, the computer-assisted pharmacokinetic dosing method should be used in septic surgical patients whose renal function is subject to sudden and unexpected changes. J Pharmacol Exp Ther, 1982 Feb, 220(2), 287 - 92 Aminoglycoside inhibition of a renal phosphatidylinositol phospholipase C; Lipsky JJ et al.; Aminoglycosides are able to inhibit phosphatidylinositol phospholipase C activity in a soluble fraction of rat renal tissue . The Km of the enzyme with respect to phosphatidylinositol is 0.53 mM and Vmax was 0.671 mumol of phosphatidylinositol cleaved per hr per mg of protein . The enzyme is calcium activated and inhibited by ethylene glycol bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid . Streptomycin, amikacin, kanamycin, tobramycin, gentamicin and neomycin inhibit enzyme activity in the same rank order as their ability to produce nephrotoxicity . The 50% inhibitory concentrations ranged from 0.03 mM for neomycin to 0.38 mM for streptomycin . Lineweaver Burk plots indicate competitive inhibition with a possible relation to the calcium activation . It is possible that aminoglycosides may inhibit phosphatidylinositol phospholipase C in vivo and that this inhibition may be related to the nephrotoxicity of aminoglycosides. Eur J Clin Pharmacol, 1982, 23(2), 155 - 60 Modification in the pharmacokinetics of amikacin during development; Lanao JM et al.; The disposition kinetics of a single i.v . dose of amikacin was studied in 6 neonates (6-25 days old), 10 infants (4-18 months) and 8 young children (3-11 years) . There was a progressive change in the distribution and elimination kinetics during development . The distribution coefficient of the antibiotic averaged of 0.429, 0.320 and 0.210 l/kg in the newborns, infants and young children, respectively and serum half-life (t1/2 beta) in these three groups averaged 2.812, 1.803 and 1.196 h, respectively . Significant differences in certain pharmacokinetic parameters were found between the values in paediatric patients and in adults receiving the same dose . A linear relationship was established between the distribution volume of the antibiotic and the weight of the patients, as defined by the following equation: Vdss (1) = 0.976 + 0.140 . TBW (kg); r = 0.954 . The results suggest that a regimen of very frequent administrations should be employed in infants and young children in order to maintain a therapeutic level throughout treatment. Chemotherapy, 1982, 28(1), 1 - 5 In vitro susceptibility of mycobacteria species other than Mycobacterium tuberculosis to amikacin, cephalosporins and cefoxitin; Haas H et al.; The susceptibility of different species of mycobacteria, other than M . tuberculosis, to a range of cephalosporins and to amikacin was studied . Susceptibility patterns varied with species . M . fortuitum, M . marinum and M . szulgai were the most susceptible species to amikacin and to cefoxitin, where as M . kansasii, M . scrofulaceum and MAIS complex the most resistant . Cefoxitin appears to be much more active against mycobacteria than the other cephalosporins used in this study . Most of the cefoxitin-sensitive mycobacteria were inhibited by concentrations which can be easily attained in serum on standard dosage schedules. Clin Ther, 1982, 5(2), 155 - 62 A survey of prospective, controlled clinical trials of gentamicin, tobramycin, amikacin, and netilmicin; Cone LA; Data from 24 prospective, controlled clinical studies of the aminoglycosides gentamicin, tobramycin, amikacin, and netilmicin are reviewed . According to these findings, netilmicin is the safest and most effective of the four types (P less than 0.01, both comparisons), and gentamicin is more effective than tobramycin (P less than 0.05) and less ototoxic than amikacin (P less than 0.05). Urol Int, 1982, 37(4), 221 - 35 Quantitative histophotometry analysing significant inductive and alterative effects of aminoglycoside application (gentamicin, tobramycin, amikacin) upon tubular kidney proteins; Heinert G et al.; In order to evaluate quantitative changes in kidney proteins, computer-assisted histophotometry of tissues was performed . Kidney marker enzyme concentrations were considered to be involved in inductive and alterative developments in the proximal tubule . These effects were caused by the administration of aminoglycosides . Indicator enzymes of the proximal tubule such as membrane-bound alkaline phosphatase (AP) and alanine-aminopeptidase (AAP) as well as lysosomal beta-glucuronidase (beta-Gl) were stained in kidney tissues . Graphic monitoring and digital display of kidney cortex sections were registered by electronic image analysis using the 'Micro-Videomat' 2 system . As an experimental design, 160 kidneys of Wistar rats were studied . Their kidneys were analyzed after one, two and three intravenous applications of gentamicin, 25 mg/kg/day, or tobramycin, 25 mg/kg/day, or amikacin, 50 mg/kg/day, on consecutive days . In a fourth test group, the kidneys were examined after the third application and a 5-day recovery period . Concentrations of tubular marker enzymes were significantly increased (2p less than 0.01, Wilcoxon test) after two applications of gentamicin: AP 37.6%, AAP 6.3% and beta-Gl 11.8% . Contrary to these findings, after two injections of tobramycin or amikacin only slight alterations were documented: tobramycin, AP 14.5%, AAP -0.1% and beta-Gl 0.4%; amikacin, AP 6.0% and AAP 4.2% . The studies indicate that tobramycin induces less severe nephrotoxic and inductive reaction than gentamicin and partly than amikacin in doses administered during our experiments . In all cases, enzyme activities studied were nearly normalized after three applications of aminoglycosides and a recovery period of 5 days . Quantitative computer-assisted evaluation of the proteins located in the tubule appears to be a tool for monitoring the degree of alterations caused by enzyme induction, enzyme release and excretion of kidney proteins. Antimicrob Agents Chemother, 1981 Nov, 20(5), 583 - 6 Intraventricular levels of amikacin after intravenous administration; Yogev R et al.; Serum and ventricular fluid pharmacokinetic data for amikacin were evaluated prospectively in 10 hydrocephalic children with suspected ventriculitis . After the fourth or fifth intravenous 7.5-mg/kg dose of amikacin given every 8 h, mean peak serum levels were 24.3 +/- 3.2 microgram/ml (achieved at 0.5 h) with a calculated half-life of 2.2 +/- 1.1 h . Mean peak ventricular fluid levels in five patients with bacterial infection were 6.1 +/- 2.0 microgram/ml (achieved at 3 h) . In the remaining five patients without bacterial ventriculitis, very low levels (less than or equal to 0.7 microgram/ml) of amikacin were detected . Ventricular fluid pleocytosis was directly correlated and glucose levels were inversely correlated with penetration of amikacin . Systemic therapy with amikacin may be the treatment of choice for children with ventriculitis meningitis caused by bacteria which are highly susceptible to this drug, thereby permitting the avoidance of the potentially hazardous intraventricular route of administration. Antimicrob Agents Chemother, 1981 Oct, 20(4), 515 - 7 Concentrations of kanamycin and amikacin in human gallbladder bile and wall; Hansbrough JF et al.; The concentrations of amikacin and kanamycin were determined in the serum, gallbladder bile, and gallbladder wall of 20 patients undergoing elective cholecystectomy . Of 20 patients, 14 received 500 mg of amikacin intramuscularly and 6 received 500 mg of kanamycin intramuscularly at various times before surgery . In patients receiving kanamycin, detectable levels appeared in bile within 90 min after drug administration, and in five of six patients concentrations ranged from 1.9 to 23 micrograms/ml . Levels of kanamycin in gallbladder wall ranged from 8.0 to 14 micrograms/g . In patients receiving amikacin, detectable levels appeared in bile within 48 min after drug administration and ranged from 1.3 to 7.5 micrograms/ml in 12 of 14 patients . Levels of amikacin in gallbladder wall ranged from 4.7 to 34 micrograms/g . The presence of an obstructed cystic duct did not preclude the entry of either antibiotic into gallbladder bile, and this may reflect passage of antibiotic through the gallbladder wall rather than accumulation via bile secretion. Res Commun Chem Pathol Pharmacol, 1981 Oct, 34(1), 89 - 95 The effect of aminoglycosides on glomerular endothelium: a comparative study; Luft FC et al.; In addition to being tubular nephrotoxins, the aminoglycosides are known to injure the glomerular endothelium by decreasing the diameter and density of endothelial fenestrae . To determine whether or not these changes correlate with the rank order of toxicity we compared in rats the effects of netilmicin, tobramycin, and amikacin on renal function, tubular and glomerular ultrastructure, at 10 and 25 times the recommended human dose . According to measurements of glomerular filtration rate their rank order of toxicity, in increasing severity was: netilmicin, tobramycin, and amikacin . The same order of effect was observed on glomerular ultrastructure . Thus glomerular structural changes correspond to glomerular functional changes in this model. Clin Pharmacol Ther, 1981 Sep, 30(3), 414 - 21 Prediction of creatinine clearance from serum creatinine concentration based on lean body mass; Hallynck T et al.; An equation for predicting endogenous creatinine clearance (CrCl) in adults and children (with both stable and unstable renal function) from serum creatinine concentration is presented . The predictions are compared with four other available estimating methods, bases on values in 110 subjects with renal impairment of widely differing degrees . In patients with stable and with unstable renal function the corelaion between measured and predicted CrCl was better with the new equation . In patients with rapid changing renal function the new equation resulted in accurate predictions CrCl within a few hours after the change, as opposed to several with the other methods . The elimination rate constant of the aminoglycoside antibiotic amikacin correlated more precisely with CrCl values estimated from the new equation that with those measured doing 24 hr or with the other prediction methods. Kidney Int, 1981 Jul, 20(1), 115 - 21 Pharmacokinetics of amikacin in children with normal and impaired renal function; Lanao JM et al.; The pharmacokinetics of the antibiotic amikacin sulfate were studied in eight children with normal renal function and in ten children with varying degrees of renal impairment . All patients received a single i.v . dose of 7.5 mg/kg of the antibiotic . Amikacin follows a two-compartment open-kinetic model . The serum half-life, which in children with normal renal function has an average value of 1 hour, reached values of 14 hours in children with severe renal impairment . A lineal relationship is established between the beta constant and the creatinine clearance (Clcr) according to the equation beta = 0.001 + 0.005.Clcr, with r = 0,818 . From thie equation, the dosage interval is modified to maintain the serum concentrations of the antibiotic within the therapeutic interval. Immunology, 1981 Jul, 43(3), 459 - 65 The effect of combined chemotherapy on suppressor T-cell activity in Mycobacterium simiae-infected mice; Watson SR et al.; Specific pathogen-free B6D2 mice were infected with 10(6) or 10(8) viable Mycobacterium bovis (BCG Pasteur) or Mycobacterium simiae and the in vivo growth curves were correlated with the levels of delayed hypersensitivity developed against a cytoplasmic protein antigen (CPA) injected into a hind footpad at increasing time intervals after infection . Half of the heavily infected, anergic mice were placed on a regimen of 10 mg of rifampin, 5 mg of amikacin and 2 mg of clofazimine per 100 ml of drinking water 2 or 8 weeks into the infection . The number of viable mycobacteria recovered from the lungs and spleens of the treated mice (compared with the corresponding drug-free controls) were reduced by up to 10,000-fold over a 3-month treatment period . Spleen cells were harvested at increasing time intervals from the drug-treated and control mice and T-cell enriched suspensions were tested for blastogenic responsiveness to phytohaemagglutinin (PHA) and to the specific CPA mitogen . The early (day 14) peak in tritiated thymidine ({3H}-TdR) uptake was followed by a sharp drop to near background levels . Cell-mixing experiments demonstrated the presence of a suppressor T-cell population in the heavily infected spleens of the M . simiae-infected mice . The suppressor-cell effect was substantially reduced following combined drug therapy although the specific CPA-mediated response was less affected than the non-specific PHA-mediated response. Antimicrob Agents Chemother, 1981 May, 19(5), 696 - 9 Increase of the intestinal absorption of gentamicin and amikacin by a nonionic surfactant; Rubinstein A et al.; This study was concerned with the effect of Cetomacrogol (polyethylene glycol 1000 monocetyl ether), a nonionic surfactant, on the absorption of gentamicin and amikacin from the gastrointestinal tract of rats . A 200-mg dose of Cetomacrogol coadministered orally with 10 mg of gentamicin resulted in a mean peak gentamicin blood concentration of 14.1 microgram/ml, compared with 67.8 microgram/mg when the same gentamicin dose was administered intramuscularly . The area under the curve after administration of the oral mixture was 23% of that after the intramuscular dose . The rectal administration of the mixture resulted in a mean peak gentamicin blood level of 8.2 micrograms/ml, compares to 16.5 microgram/ml when the mixture was administered orally . A 50-mg dose of amikacin coadministered orally with 200 mg of Cetomacrogol resulted in a mean peak amikacin blood level of 13.3 microgram/ml, compared to 310 microgram/ml when this amikacin dose was administered intramuscularly . Cetomacrogol augments the intestinal absorption of gentamicin and amikacin in rats . If the toxicity of the combination in humans is limited, the combination may be potentially clinically useful. Am J Hosp Pharm, 1981 Apr, 38(4), 524 - 9 Collaborative clinical pharmacokinetic services; Maddox RR et al.; A program for routine pharmacokinetic interpretation of serum analyses of gentamicin, tobramycin, amikacin, phenytoin, phenobarbital, theophylline, lidocaine, digoxin, quinidine, and procainamide at the Medical University of South Carolina Hospital is described . Results of all analyses of serum for the drugs listed are evaluated by a pharmacist trained in clinical pharmacokinetics . Patient variables relevant to the determination of drug serum concentrations, drug elimination, distribution, and dosage are given appropriate consideration in each evaluation . A summary of the pharmacokinetic interpretation and any necessary modification of drug dosage regimens are then written into the progress notes of the patients' medical records . Approximately 12 patients and 20 drug concentrations are evaluated each day . The average charge for te service is +35 . This service, which is reimbursed by third-party carriers, has resulted in improved use of laboratory personnel, equipment, and time and has provided a framework for education and research as well as a mechanism for direct contributions to patient care by the pharmacist. Antimicrob Agents Chemother, 1981 Apr, 19(4), 567 - 70 Assays of serum aminoglycoside levels by BACTEC 460 in the presence of cefamandole and cefoxitin; Phillips LE et al.; The effects of cefamandole and cefoxitin on the assays of serum containing gentamicin, tobramycin, or amikacin by the BACTEC 460 (Johnston Laboratories, Cockeysville, Md.) were studied . The results were analyzed to determine whether the presence of the test substances, cefamandole or cefoxitin, caused a statistically different mean value of aminoglycoside or increase in variance as compared with serum assayed in their absence . The results were then considered in light of medical significance to see whether the difference observed would have any real effect on patient care . The results of each analyses dictate that serum of patients treated with both amikacin and cefamandole be tested in triplicate. J Pharm Sci, 1981 Apr, 70(4), 449 - 52 Effect of dosing volume on intramuscular absorption rate of aminoglycosides; Pfeffer M et al.; The Loo-Riegelman method was applied to serum amikacin level data after intravenous and intramuscular administration . Intramuscular amikacin absorption can be described by first-order kinetics, but the absorption rate constant decreased from 1.95 hr-1 at a 125-mg dose to 1.00 hr-1 at a 750-mg dose . This rate change apparently is a physical phenomenon due to differing dosing volumes at different doses and attendant changes in the surface area to volume ratio at the injection site . Amikacin absorption rates on intramuscular injection can be maximized by giving several smaller injections rather than a single larger injection . This phenomenon should be generally observed with aminoglycoside antibiotics and could be partly responsible for reported variations in the absorption rate and the poor predictability of serum concentrations. Antimicrob Agents Chemother, 1981 Feb, 19(2), 352 - 4 Amikacin sulfate levels in human serum and bile; Bermudez RH et al.; Amikacin levels in blood and bile were measured in 10 patients who underwent cholecystectomy and T-tube drainage . Each patient received 500 mg of amikacin intravenously 12 h preoperatively, during surgery, and every 12 h thereafter for four more doses . Average levels of amikacin in bile were 8.3 micrograms/ml at 1 h after the intraoperative dose, with a bile/serum ratio of 0.44 . Postoperative doses at 1 h produced levels in bile of 3.8 to 4.2 micrograms/ml, with a bile/serum ratio of 0.15 to 0.22 . Levels in bile decreased at a rate lower than levels in blood, and bile/serum ratios increased from 0.54 at 2 h to 0.93 at 12 h . Amikacin accumulated in bile at 6 h after the intravenous dose. Eur J Clin Pharmacol, 1981, 19(5), 367 - 70 Influence of the route of administration on the pharmacokinetics of amikacin; Lanao JM et al.; The pharmacokinetics of amikacin was studied in 17 hospitalized patients with normal renal function (creatinine clearance greater than 90 ml/min), after the administration of a single dose of 7.5 mg/kg body weight . In 10 patients the antibiotic was administered intravenously and in the other 7 it was injected intramuscularly . After i.v . administration, the antibiotic followed an open two-compartment kinetic model, and after i.m . administration it followed a single compartment kinetic model . The route of administration did not significantly modify the pharmacokinetic parameters of amikacin . On the basis of the pharmacokinetic parameters thus established, an intravenous infusion for therapeutic use should have an administration rate of 2.5 {mg/kg/h} and a duration of 6 h. Acta Otolaryngol Suppl, 1981, 383, 1 - 19 Aminoglycoside-induced cochlear pathology in man; Johnsson LG et al.; Temporal bones from five patients with hearing loss as a result of aminoglycoside treatment were examined by the method of microdissection and surface preparations, followed by celloidin embedding and serial sectioning of the modiolus . Three patients had received the newer antibiotics, gentamicin, tobramycin, and amikacin; the other two neomycin . In the cochleas from two patients of the first group there was only a small loss of hair cells, restricted to the lower end of the basal turn . The third, who had been treated with several antibiotics over a longer period of time, showed more extensive but strikingly asymmetrical patterns of degeneration in the two ears . This patient, as well as the fourth, who had received neomycin during peritoneal lavage, had numerous patchy areas of complete disappearance of Corti's organ in the basal turn, with incipient degeneration of the distal ends of the nerve fibers in adjacent portions of the osseous spiral lamina . The fifth patient, who had become deaf after prolonged treatment with neomycin by mouth, showed a complete loss of cochlear hair cells . Nerve fibers were present only in the middle and upper turns, where supporting cells remained . Midmodiolar sections showed a proportionately much greater loss of the distal than of the proximal processes of the cells of the spiral ganglion . These findings underscore once again the special hazard for the inner ear that is associated with the clinical use of neomycin, regardless of the route of administration. Schweiz Med Wochenschr, 1980 Dec 6, 110(49), 1886 - 7 {Protection against ascending pyelonephritis by means of preventive aminoglucoside administration}; Bille J et al.; Accumulated and persistent gentamicin in the kidney, when given prophylactically, affords protection against ascending obstructive E . coli pyelonephritis . Similar protection was observed after administration of tobramycin, netilmicine and amikacin, aminoglucoside antibiotics that accumulate to varying degrees in the renal parenchyma. Antimicrob Agents Chemother, 1980 Dec, 18(6), 983 - 5 Comparative nephrotoxicities of dibekacin, amikacin, and gentamicin in a rat model; Rankin LI et al.; The nephrotoxicity of dibekacin was compared with those of gentamicin and amikacin in a rat model . The doses used were 3, 10, and 30 times the suggested human therapeutic dose on a weight basis . Indices of glomerular and tubular function failed to clearly differentiate the drugs . Dibekacin and gentamicin produced equally severe injury to the renal tissue . Slightly less damage occurred with amikacin. J Environ Pathol Toxicol, 1980 Nov, 4(5-6), 277 - 91 Amikacin nephrotoxicity in the rat; Houghton DC et al.; When amikacin was administered to Fischer rats at a dose of 120 mg/kg/day for up to 14 days, renal proximal tubule cells became vacuolated, but BUN and creatinine remained normal . Renal cortical drug levels rose steadily throughout the treatment period . When, in a second trial of the same duration, the drug dose was tripled, focal proximal tubular necrosis, then regeneration, occurred and the animals became azotemic . Tissue drug concentrations peaked and began to decline during the treatment period, having reached levels more than three times higher than achieved at the lower dose . Ultrastructural changes were similar to those observed with other aminoglycosides . The results indicate that amikacin is less nephrotoxic than gentamicin and more toxin than tobramycin and netilmicin in the Fischer rat. Science, 1980 Oct 3, 210(4465), 83 - 6 Acoustic responses after total destruction of the cochlear receptor: brainstem and auditory cortex; Cazals Y et al.; Acoustically evoked neural activity has been recorded from the brainstem and auditory cortex of guinea pigs after complete destruction of the organ of Corti by the aminoglycosidic antibiotic amikacin . These responses to sound differ in important respects from the evoked potentials normally recorded from the auditory pathways . At the brainstem level they resemble the potentials reported by others after stimulation of the vestibular nerve. Antimicrob Agents Chemother, 1980 Aug, 18(2), 264 - 8 Substrate-labeled fluorescent immunoassay for amikacin in human serum; Thompson SG et al.; A homogeneous substrate-labeled fluorescent immunoassay has been developed to measure amikacin levels in human serum . Amikacin is covalently labeled with the fluorogenic enzyme substrate beta-galactosyl-umbelliferone . This beta-galactosyl-umbelliferone-amikacin conjugate is nonfluorescent under assay conditions until it is hydrolyzed by beta-galactosidase to yield a fluorescent product . When antiserum to amikacin binds the substrate-labeled drug, the antibody complex formation inhibits hydrolysis of the fluorogenic substrate . Reaction mixtures containing a constant level of substrate-labeled amikacin and a limiting amount of antiserum enable labeled and unlabeled amikacin to compete for the antibody-binding sites . Unbound substrate-labeled drug is hydrolyzed by the enzyme to release a fluorescent product that is proportional to the unlabeled amikacin concentration . The amikacin levels found in clinical serum samples with this method were comparable (r = 0.987) to those obtained by radioimmunoassay . The fluorescent immunoassay is rapid and simple to perform and requires only 2 microliters of serum. Aust N Z J Med, 1980 Aug, 10(4), 440 - 3 Mycobacterium fortuitum: an unsuspected cause of synovitis and osteomyelitis; Williams GV; Two men with progressive synovitis and osteomyelitis of the wrist were found to have infection with Mycobacterium fortuitum . Immunological defects were demonstrated in both cases in association with renal failure and renal transplantation respectively . Failure of appropriate antibiotic therapy to eradicate infection necessitated amputation in one case . M . fortuitum is frequently sensitive to only amikacin or kanamycin . Treatment with amikacin alone was unsuccessful . This organism is widespread in the environment and may need to be considered in undiagnosed chronic infection in the immunologically suspectible host, as it poses unusual problems in diagnosis and therapy. J Clin Microbiol, 1980 Jul, 12(1), 79 - 83 Prevalence of gentamicin- and amikacin-resistant bacteria in sink drains; Perryman FA et al.; Sink drains from the Veterans Administration Medical Center, University of Oklahoma Health Sciences Center, and the Oklahoma City community were selectively cultured for gentamicin- and amikacin-resistant bacteria . Aminoglycoside-resistant organisms were found in 86% (Veterans Administration Medical Center, 88%; University of Oklahoma Health Sciences Center, 88%; and Oklahoma City community, 77%) of all 233 sink drains sampled . Of 207 sink drains harboring aminoglycoside-resistent organisms, 99% of the organisms were gentamicin resistant and 82% were amikacin resistant . These data suggest that aminoglycoside-resistent organisms are commonly present in the environment. Antimicrob Agents Chemother, 1980 Jul, 18(1), 176 - 81 Comparative low-dose nephrotoxicities of gentamicin, tobramycin, and amikacin; Hottendorf GH et al.; Most investigations of the comparative nephrotoxicities of aminoglycosides in animals have utilized large multiples of the human dose . Furthermore, many of these assessments have used only one or two dose levels and have not described a dose-response comparison among antibiotics . Because of this lack of comparative dose-response data over a range of low multiples of the human dose, the nephrotoxicities of gentamicin, tobramycin, and amikacin were investigated in 180 rats, utilizing doses ranging from one to seven times the equivalent human clinical doses . Histopathological evaluations of both kidneys from each rat were scored without knowledge of the treatment, and statistical analyses of the results indicated that a linear and parallel dose-response relationship existed for each drug, the relative nephrotoxicity over the range of doses analyzed was gentamicin > tobramycin > amikacin (P = 0.0001), and, unlike amikacin, the human dose equivalents (milligrams per kilogram) of gentamicin and tobramycin were significantly nephrotoxic in rats (P < 0.05). Am J Hosp Pharm, 1980 Apr, 37(4), 519 - 22 Amikacin pharmacokinetics in morbidly obese patients; Bauer LA et al.; The pharmacokinetics of single-dose amikacin sulfate was studied in seven morbidly obese patients to determine the fraction of fat weight (FW) that, when added to ideal body weight (IBW), will normalize the volume of distribution . Seven patients (mean total body weight of 166.5 kg) were each given a 1,250-g intravenous injection of amikacin . Amikacin serum levels over eight hours were measured by radioimmunoassay . A correction factor (CF) of 0.38 was found to normalize the patients' volume of distribution (Varea) to 0.26 liters/kg, when added to the patients' IBW . There was no significant difference between peak amikacin levels predicted using the actual Varea and using the Varea plus the CF . Predictions using the actual Varea and those using Varea estimated by ideal body weight were significantly different . In morbidly obese patients, peak amikacin serum levels can be predicted best when a volume of distribution based on IBW plus a correction factor of 38% of FW is used. Acta Pharmacol Toxicol (Copenh), 1980 Apr, 46(4), 289 - 92 Comparative ototoxic effects of RU 25434, amikacin and neomycin in guinea-pigs; N'guyen P et al.; The ototoxic effects of RU 25434, a new semi-synthetic aminoglycoside antibiotic, were compared to those of amikacin and neomycin . Experiments were performed in adult and new-born guinea-pigs, ototoxicity being assessed by Preyer's reflex response and the measurement of the cochlear microphonic potentials at the end of treatment . The well known ototoxicity of neomycin was observed and RU 25434 appeared to be relatively less toxic than amikacin . The use of new-born guinea-pigs seem to be particularly suitable for this type of study because of their apparent sensitivity to ototoxicity. J Pediatr, 1980 Apr, 96(4), 721 - 6 Serum salicylate levels and right-to-left ductus shunts in newborn infants with persistent pulmonary hypertension; Perkin RM et al.; Although a right-to-left shunt via a patent ductus arteriosus is one criterion for the diagnosis of persistent pulmonary hypertension of the newborn infant, it cannot be demonstrated by simultaneous pre- and postductus arteriosus blood oxygen tensions in many infants with the clinical syndrome . In animals, exposure of the fetal ductus arteriosus to salicylates causes contriction and results in pulmonary hypertension . We postulated that maternal ingestion of salicylates and premature closure of the ductus arteriosus may explain why some infants with PPHN do not have right-to-left ductus shunts . Therefore, we studied serum salicylate levels in six groups of infants: I, normal infants' cord blood (0.73 +/- 0.44 mg/dl, N = 20); Ia, normal infants at 24 to 36 hours of age (0.08 +/- 0.1 mg/dl, N = 5): II, other cardiopulmonary diseases with no right-to-left ductus shunt (2.08 +/- 1.74 mg/dl, N = 26); III, other cardiopulmonary diseases and right-to-left ductus shunt (2.34 +/- 1.70 mg/dl, delta Pao2 70 +/- 71 mm Hg, N = 6); IV, PPHN and right-to-left ductus shunt (1.86 +/- 1.51 mg/dl, delta Pao2 39.6 +/- 58.9 mm Hg, N = 5); V, PPHN without right-to-left ductus shunt (7.77 +/- 5.18 mg/dl, delta Pao2 2.2 +/- 1.5 mm Hg, N = 6) . Serum salicylate levels were significantly greater (P less than 0.01) in infants with PPHN without right-to-left ductus shunt, indicating that the ductus arteriosus may have been closed prematurely . No other factor, including serum bilirubin, amikacin, ampicillin, or furosemide levels, could be found to account for the difference in serum salicylate levels . Premature closure of the ductus arteriosus secondary to maternal ingestion of salicylates may be one cause of PPHN and may explain the absence of right-to-left ductus shunting in some infants with the clinical syndrome. Acta Otolaryngol, 1980 Mar-Apr, 89(3-4), 376 - 83 Electrophysiological monitoring of the cochlea during and after total destruction of the organ of corti; Aran JM et al.; A series of acoustically evoked potentials can be recorded from the cochlea up to the auditory cortex in guinea pigs where the organ of Corti has been totally destroyed after extensive treatment with amikacin, but where some of the spiral ganglion neurons always remain and where the vestibular receptors are only slightly affected . The cochlear responses have been monitored in guinea pigs permanently implanted with a round window electrode and receiving such treatment . The normal auditory nerve compound action potential disappears within a few days, while the very typical response (diphasic, short latency (0.3 ms) small amplitude) appears . This response then remains remarkably constant in time as far as we could observe (up to almost one year) . This response might be a component of the normal response, undiscernible under normal conditions but revealed by the selective impairment of the labyrinth by amikacin, in contrast to the global effect of every other known otodestructive agent . Some basic questions still remain: which fibres are effectively stimulated (cochlear or vestibular), what are their central projections, and what kind of sensation is conceivably associated with these responses? Infection, 1980, 8 Suppl 3, S 239 - 42 Evaluation of amikacin dosage regimes in the low and very low birthweight newborn; Cookson B et al.; The recommended neonatal dosage regime for amikacin of 15 mg/kg/day was found to be unsatisfactory in four neonates and a loading dose of 10 mg/kg did not improve levels in two further newborns with normal renal function . Fourteen neonates on 20 mg/kg/day regime achieved satisfactory levels; peak values were 21.5 +/- 4.5 microgram/ml and trough levels 3.34 +/- 2.05 microgram/ml . Peak time ranged from 17 to 60 minutes and varied with the dose given . The half-life was related to plasma creatinine, urea, post-natal age and weight . Thirteen neonates with pre-existing renal impairment were managed by alteration of dosage interval or quantity given . Side-effects were confined to eosinophilia in six infants, and no definite nephrotoxicity or gross eighth nerve damage was demonstrated. Antimicrob Agents Chemother, 1979 Dec, 16(6), 829 - 32 Amikacin pharmacokinetics in pediatric patients with malignancy; Cleary TG et al.; The pharmacokinetics of amikacin were evaluated in 50 pediatric patients (1 to 17 years of age) with malignancies and normal renal function . Dosage regimens of 5 mg/kg per dose were administered intravenously (i) over 30 min every 8 h, (ii) over 60 min every 8 h, and (iii) over 60 min every 6 h . Administration of amikacin over 30 min produced concentrations in serum of 29.3 +/- 5.7 micrograms/ml at the end of the infusion and subtherapeutic concentrations 4 h after the infusion . The regimen of 20 mg/kg per 24 h, divided into doses given every 6 h infused over 60 min, achieved concentrations in serum at the end of the infusion of 17.2 +/- 1.7 micrograms/ml and at 6 h of 1.2 +/- 0.3 microgram/ml . The serum half-life was 1.24 +/- 0.09 h, volume of distribution was 0.26 +/- 0.02 liter/kg, and total body clearance rate was 131 +/- 10 ml/min per 1.73 m2 . No accumulation of amikacin was noted, and no significant side effects could be attributed to the drug . This study suggests that the optimal initial dosage regimen of amikacin in children is 20 mg/kg per 24 h administered in equal doses every 6 h over 60 min; however, optimal therapy requires individualization of dosage based on measured serum concentrations and susceptibility data on bacterial pathogens isolated. Clin Pharmacol Ther, 1979 Nov, 26(5), 635 - 40 Multiple-dose amikacin kinetics in pediatric oncology patients; Kramer WG et al.; Amikacin kinetics was studied in 8 pediatric oncology patients who received the drug by intravenous infusion over 30 or 60 min at a dose of 5 mg/kg every 6 or 8 hr . This regimen is recommended but, due to patient variability, patients should be monitored . Dosing intervals during 1 or 2 and 3 or 4 days of therapy were studied with serum samples collected before and at the end of the infusion and serially to the end of the dosing interval . The data appeared consistent with and were analyzed according to 1-compartment model . An equation describing serum concentration with time for the multiple-dose case was fit to each patient's multiple-interval data with nonlinear regression . Half-life averaged 1.2 hr . volume of distribution 0.24 l/kg, and total body clearance 109 ml/min/1.73 m2 or 2.51 ml/min/kg . The volume of distribution and the clearance are greater than reported for adults and probably account for the larger dose needed to achieve and maintain therapeutic levels . Although the total daily dose was greater than previously reported, there were no signs of toxicity, although therapuetic concentrations were maintained. J Antimicrob Chemother, 1979 Sep, 5(5), 527 - 30 Amikacin dosage in the preterm newborn; Want SV et al.; Twenty-two preterm infants of gestational age 26 to 34 weeks were treated with amikacin for suspected bacterial infection, using a dose of 7.5 mg/kg, 12-hourly, intra muscularly . Blood levels were measured using a radio-immunoassay kit capable of giving results within 4 h . One-hour peak levels showed wide variation and the mean level one hour after the first dose was 18.2 mg/1; in severe infections an initial loading dose of 10 mg/kg is therefore recommended . Trough levels in individual infants also varied considerably from day to day, but showed no overall accumulation . There was no obvious adverse effect on hepatic or renal function. Am J Hosp Pharm, 1979 Sep, 36(9), 1209 - 11 Aminoglycoside use monitored by clinical pharmaceutical services; Barriere SL et al.; A pharmacy-infectious diseases program designed to promote the rational use of, and decrease the adverse reactions attributed to, amikacin and tobramycin is described . Requests for amikacin and tobramycin were screened initially by a pharmacist and later reviewed by an infectious disease physician . When the appropriateness of amikacin or tobramycin use was questionable, the drug was released pending review of the order by the chief of infectious diseases . Pharmacists, in consultation with the infectious diseases service, made recommendations for alternative antibiotic therapy or dosage regimens, provided drug education to prescribing physicians and nurses, and aided in monitoring efficacy and toxicity of therapy . During a two-year period, 12 patients received tobramycin and 42 patients received amikacin . The drugs were discontinued as recommended in the 12 patients for whom culture results were negative or indicated sensitivity to other antibiotics . Two initial requests for the drugs were denied . No incidents of renal impairment were definitely associated with tobramycin or amikacin use . During an 18-month portion of the study, the two drugs accounted for approximately 2% of the hospital's total aminoglycoside c