Tobramycin-impregnated calcium sulfate pellets for the treatment of chronic osteomyelitis in children and adolescents.

The aim of this work was to evaluate the outcome and efficacy of treatment in a homogeneous group of skeletally immature patients with chronic osteomyelitis of the long bones managed by a combination of radical debridement and insertion of tobramycin-impregnated calcium sulfate pellets to fill the bone defect in a single-stage procedure. Between 2011 and 2016, 12 skeletally immature patients were treated surgically by the reported technique. Single-stage surgery using tobramycin-impregnated calcium sulfate pellets in association with systemic antibiotic therapy yields satisfactory outcomes in skeletally immature children presenting chronic osteomyelitis by reducing the risk of occurrence of comorbidities, hospital stays, and healthcare costs.

Development of Culture Medium for the Isolation of Flavobacterium and Chryseobacterium from Rhizosphere Soil.

An effective medium designated phosphate separately autoclaved Reasoner's 2A supplemented with cycloheximide and tobramycin (PSR2A-C/T) has been developed for the isolation of Flavobacterium and Chryseobacterium strains from the plant rhizosphere. It consists of Reasoner's 2A agar (R2A) prepared by autoclaving phosphate and agar separately and supplementing with 50 mg L(-1) cycloheximide and 1 mg L(-1) tobramycin. A comparison was made among the following nine media: PSR2A-C/T, PSR2A-C/T supplemented with NaCl, R2A agar, R2A agar supplemented with cycloheximide and tobramycin, 1/4-strength tryptic soy agar (TSA), 1/10-strength TSA, soil-extract agar, Schaedler anaerobe agar (SAA), and SAA supplemented with gramicidin, for the recovery of Flavobacterium and Chryseobacterium strains from the Welsh onion rhizosphere. Flavobacterium strains were only isolated on PSR2A-C/T, and the recovery rate of Chryseobacterium strains was higher from PSR2A-C/T than from the eight other media. In order to confirm the effectiveness of PSR2A-C/T, bacteria were isolated from onion rhizosphere soil with this medium. Flavobacterium and Chryseobacterium strains were successfully isolated from this sample at a similar rate to that from the Welsh onion rhizosphere.

Development and characterization of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery.

OBJECTIVE: This study deals with the preparation and evaluation of a pluronic lecithin organogel (PLO gel) containing ricinoleic acid for the transdermal eyelid delivery of dexamethasone and tobramycin. METHODS: Five different PLO gel formulations (F1, F2, F3, F4 and F5) containing tobramycin (0.3%) and dexamethasone (0.1%) were prepared and compared to a conventional PLO gel (light mineral oil PLO gel, F6) with respect to physical appearance and viscosity. The optimized ricinoleic acid PLO gel formulation (F2) was further characterized for pH, gelation temperature, morphology and drug content. Ex vivo permeability of dexamethasone and bactericidal activity of tobramycin from formulation F2 was tested, and values were compared to the marketed Tobradex® eye ointment. RESULTS: No apparent changes in the physical appearance and consistency were observed when ricinoleic acid was used as the oil phase. The pH of the optimized ricinoleic acid PLO gel (formulation F2) was found to be 6.54 with a gelation temperature of 31 °C. The drug content of tobramycin and dexamethasone were found to be 102.8% and 100.14%, respectively. The penetration profile of dexamethasone from formulation F2 was found to be much higher than the marketed Tobradex® eye ointment. F2 showed a better antimicrobial activity and higher zones of inhibition when compared to the marketed Tobradex® eye ointment. CONCLUSION: The findings of this investigation indicate that the ricinoleic acid PLO gel has the potential for use as a transdermal eyelid delivery system.

In vitro interference of Hyptis martiusii Benth. & chlorpromazine against an aminoglycoside-resistant Escherichia coli.

The antibacterial and synergistic activity of the ethanol extract from Hyptis martiusii Benth. was assayed by microdillution. The growth of two isolates of Escherichia coli tested was inhibited by the extract. The minimum inhibitory and minimum bactericidal concentrations (MIC and MBC) values ranged from 512 and >1024 microg/ml for the E. coli 27 and 1024 and > 1024 microg/ml for the E. coli ATCC8539, respectively. A synergism between this extract and all aminoglycosides assayed was demonstrated. In the same form synergism between chlorpromazine and kanamycin, amikacin and tobramycin was observed, indicating the involvement of an efflux system. Extracts from H. martiusii could be used as a source of plant derived natural products with modifying antibiotic activity and these products may interact and affect multidrug resistance systems (MDR) as efflux pumps.

The disposition of five therapeutically important antimicrobial agents in llamas.

The disposition of five therapeutic antimicrobial agents was studied in llamas (Lama glama) following intravenous bolus administration. Six llamas were each given ampicillin, tobramycin, trimethoprim, sulfamethoxazole, enrofloxacin and ceftiofur at a dose of 12 mg/kg, 1 mg/kg, 3 mg/kg, 15 mg/kg, 5 mg/kg, and 2.2 mg/kg of body weight, respectively, with a wash out period of at least 3 days between treatments. Plasma concentrations of these antimicrobial agents over 12 h following i.v. bolus dosing were determined by reverse phase HPLC. Disposition of the five antimicrobial agents was described by a two compartment open model with elimination from the central compartment, and also by non-compartmental methods. From compartmental analysis, the elimination rate constant, half-life, and apparent volume of distribution in the central compartment were determined. Statistical moment theory was used to determine noncompartmental pharmacokinetic parameters of mean residence time, clearance, and volume of distribution at steady state. Based on the disposition parameters determined, and stated assumptions of likely effective minimum inhibitory concentrations (MIC) a dose and dosing interval for each of five antimicrobial agents were suggested as 6 mg/kg every 12 h for ampicillin; 4 mg/kg once a day or 0.75 mg/kg every 8 h for tobramycin; 3.0 mg/kg/15 mg/kg every 12 h for trimethoprim/sulfamethoxazole; 5 mg/kg every 12 h for enrofloxacin; and 2.2 mg/kg every 12 h for ceftiofur sodium for llamas. Steady-state peak and trough plasma concentrations were also predicted for the drugs in this study for llamas.

Combined imipenem/cilastatin and tobramycin therapy of multiresistant Pseudomonas aeruginosa in cystic fibrosis.

Ten patients with cystic fibrosis (CF) and chronic broncho-pulmonary Pseudomonas aeruginosa infection were given imipenem/cilastatin (100 mg/kg/day) in combination with tobramycin (15 mg/kg/day). Forced vital capacity and forced expiratory volume in the first second improved significantly in nine out of ten patients, and most of the patients improved clinically. P. aeruginosa was not eradicated in any patient and resistance against imipenem developed in all patients during treatment. A concomitant increase in MIC of piperacillin and ceftazidime occurred during treatment. In-vitro bactericidal synergy of imipenem and tobramycin was noted in 57% of pretreatment isolates. Seven patients complained of adverse reactions, mainly gastrointestinal, and treatment of three patients was discontinued after 5, 8, and 12 days of therapy, because of rash or nausea and vomiting. The side effects were considered to be due to imipenem/cilastatin. Because of the rapid development of imipenem resistance despite combination therapy, the high proportion of side effects, and the risk of induction of beta-lactam resistance, imipenem/cilastatin cannot be recommended for routine treatment of CF-patients with P. aeruginosa infection.

Gentamicin nucleotidyltransferase. Stereochemical inversion at phosphorus in enzymatic 2'-deoxyadenylyl transfer to tobramycin.

Gentamicin nucleotidyltransferase-catalyzed reaction of (Sp)-[alpha-17O]dATP with tobramycin produced 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. The configuration at phosphorus in this product was shown to be Rp by chemical degradation to chiral [17O, 18O]dAMP using a stereochemically defined procedure, and determination of the configuration at phosphorus in this product. Periodate-base treatment of 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin followed by NaBH4 reduction produced (2-glyceryl)-[17O]dAMP, which upon snake venom phosphodiesterase-catalyzed hydrolysis in H(2)18O produced [17O,18O] dAMP. The configuration at phosphorus in this product was shown to be S by enzymatic phosphorylation to [17O,18O]dATP, adenylylcyclase (Bordetella pertussis)-catalyzed cyclization to 3',5'-cyclic [17O,18O]dAMP, and 31P NMR analysis of the ethyl esters. Since snake venom phosphodiesterase-catalyzed hydrolyses proceed with retention of configuration at phosphorus, (Sp)-[17O,18O]dAMP must have been produced from (Rp)-(2-glyceryl)-[17O]dAMP; and since the chemical degradation to the latter compound did not involve cleavage of any bonds to phosphorus, the initial enzymatic product must have been (Rp)-2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. Therefore, nucleotidyl transfer catalyzed by gentamicin nucleotidyl-transferase proceeds with inversion of configuration at phosphorus, and the reaction mechanism involves an uneven number of phosphotransfer steps. Inasmuch as this is an uncomplicated two-substrate group transfer reaction, the mechanism probably involves direct nucleotidyl transfer from the nucleoside triphosphate to the aminoglycoside. The B. pertussis adenylylcyclase reaction was shown to proceed with inversion at phosphorus, as has been established for other adenylylcyclases.

[Toxicity and antimicrobial properties of the new aminoglycoside antibiotic 535]. / Izuchenie toksichnosti i antimikrobnykh svoistv novogo aminoglikozidnogo antibiotika 535.

LD50 of antibiotic 535 (3'-desoxykanamycin C) on its intravenous, subcutaneous and oral administration to albino mice was 225, 1150 and at least 5000 mg/kg respectively. After a single subcutaneous administration to rabbits in a dose of 10 mg/kg antibiotic 535 was rapidly absorbed and detected in the blood and organs of the animals for 24 hours. The antibiotic was mainly excreted with the urine. Comparative investigation of the pharmacokinetics of antibiotic 535, tobramycin and kanamycin in rabbits revealed no significant differences. Antibiotic 535 showed a broad antibacterial spectrum and inhibited both grampositive and gramnegative bacteria. It was highly active against infections caused by S. aureus, E. coli and Pr. vulgaris and somewhat less active against infections caused by Ps. aeruginosa. In treatment of experimental tuberculosis of albino mice antibiotic 535 and tobramycin were inferior by their efficacy to kanamycin.

[Clinico-laboratory evaluation of the effectiveness of the new aminoglycoside antibiotic brulamycin (tobramycin) in treating surgical infections]. / Kliniko-laboratornaia otsenka éffektivnosti novogo antibiotika-aminoglikozida brulamitsina (tobramitsin) v lechenii khirurgicheskoi infektsii.

The clinico-laboratory estimation of brulamycin in the treatment of 50 patients with severe wound infections showed its high efficacy with respect to gram-negative microflora and in particular Ps. aeruginosa (94 per cent of the sensitive strains). Satisfactory into the affection foci and a long-term maintenance of its therapeutic levels in the host allowed one to recommend the antibiotic for the treatment of patients with complicated purulent affections and first of all systemic infections.

Tobramycin inactivation by carbenicillin, ticarcillin, and piperacillin.

The in vitro and in vivo inactivation of tobramycin by carbenicillin, ticarcillin, or piperacillin was investigated by the enzyme immunoassay method in clinically employed dosages. After the addition of an 80-mg dose of tobramycin to 4- to 5-g doses of a penicillin in 100 ml of 0.9% saline or distilled water, the degradation profile of tobramycin appeared to follow a biexponential pattern of decay. Remarkable losses (30 to 40%) of tobramycin combined with carbenicillin or ticarcillin were observed within 1 h, as compared with the later decline. The combination of tobramycin with piperacillin was least inactivating. When the admixture of tobramycin with carbenicillin or piperacillin used in the in vitro study was infused to six volunteers over 1 h, the observed maximum concentrations of tobramycin were on the average 66 and 74% for carbenicillin and piperacillin, respectively, of that observed after tobramycin alone was given. In contrast, the value obtained for tobramycin in combination with piperacillin was close to 90% of the control value. The elimination half-lives of tobramycin combined with the penicillins were slightly shorter than those of tobramycin alone, indicating that the interaction occurs even in patients with normal renal function.

Renal toxicity of aminoglycosides in the neonatal period.

Renal toxicity of aminoglycosides seems to be less frequent in newborn infants compared to adults even though glomerular filtration rate and tubular secretion and reabsorption mechanisms are subjected to adaptive processes during the neonatal period. In 14 infants, kinetic parameters of gentamicin were determined using an open three-compartment body model. According to the lower glomerular filtration rate, the beta-elimination phase is longer in the newborn infant compared to adults, while the gamma-elimination phase is quite similar to adult values. The calculated drug accumulation in the deep compartment (kidney) under steady-state conditions is lower in newborns compared to infants. The excretion of urinary enzymes of tubular origin, that is the lysosomal NAG (N-acetyl-beta-D-glucosaminidase), beta-glucuronidase, and the brush-border-associated AAP (alanine-aminopeptidase), GGT (gamma-glutamyl-transpeptidase), are lower in healthy newborn infants compared to older ones. The increase of AAP, for instance, during aminoglycoside therapy is less pronounced in newborn infants, especially in prematures, if compared to adult values. After end of therapy the AAP excretion decreases to normal. The calculated rate of this decrease takes place in a fashion similar to the release of drugs from the kidney (gamma-elimination phase). The data indicate that there may be a lower renal accumulation of aminoglycosides in newborn infants, which can be explained by the morphometric and functional characteristics of the newborn kidney.

Treatment of twelve burn wound infections and eight other serious infections with cefazolin and tobramycin: in vitro and in vivo evaluation.

20 patients with serious infections were treated with cefazolin and tobramycin for 9--64 days. Minimal inhibitory concentration (MIC) values and minimal bactericidal concentration (MBC) values were determined for each of the 112 clinical bacterial isolates. The median cefazolin MIC/MBC was 1.56/12.5 micrograms/ml, and the median tobramycin MIC/MBC was 6.25/25.0 micrograms/ml for all organisms studied. Median cefazolin doses of 49.0 mg/kg/day gave median peak/trough serum levels of 43.0/11.0 micrograms/ml. Median tobramycin doses of 4.3 mg/kg/day gave median peak/trough serum levels of 5.0/1.4 micrograms/ml. Checkerboard studies revealed synergy with 65% of strains. Bacteriologic and clinical success was obtained in 17 of 20 patients.

A novel mechanism of resistance to penicillin-gentamicin synergism in Streptococcus faecalis.

A patient with enterococcal endocarditis, who relapsed after repeated courses of apparently adequate treatment with ampicillin plus gentamicin, was subsequently cured with ampicillin-tobramycin therapy. The organisms isolated from this patient were strains of Streptococcus faecalis that were resistant to penicillin (or ampicillin)-gentamicin synergism but not to penicillin (or ampicillin)-tobramycin synergism. The mechanism of resistance in these strains appears to be related to a specific defect in the intracellular uptake of gentamicin (but not tobramycin) in the presence of penicillin.

Therapeutic effect of topical antibiotic on untreated eye in experimental keratitis.

We studied the systemic absorption ot topical tobramycin and amikacin in experimental Pseudomonas keratitis in guinea pigs. After giving two drops of tobramycin 40 mg/ml every 30 minutes for 24 hours to both infected eyes (the corneal epithelium having removed) the mean serum concentration was 1.5 mcg/ml. Treatment of one of the infected eyes with the same strength of tobramycin or amikacin drops did not alter the number of viable bacteria in contralateral eyes treated with saline. Tobramycin 400 mg/ml or amikacin 250 mg/ml however, decreased the number of viable bacteria in the contralateral eyes. We conclude that the therapeutic effect on the contralateral eye was the result of systemic absorption.

[Concentration in bone and haematoma of the aminoglycoside antibiotic tobramycin (author's transl)]. / Knochen- und Hämatomspiegel des Aminoglykosid-Antibiotikums Tobramycin.

Tobramycin concentrations were assayed in the rabbit in serum during surgery and in serum, haematoma and bone tissue of the condyle of the femur in the absence of surgery. After a single i. m. injection serum levels were found to be 30% higher initially than in humans, but then dropped at a faster rate to zero. The hardening haematoma appeared to slow penetration of the antibiotic. The concentration in bone tissue was dependent on vascular supply. Surgery did not show any influence on the level of the concentrations.

Tobramycin: in vitro and clinical evaluation in 30 patients.

Clinical evaluation of intramuscular tobramycin was accomplished in 30 patients with respiratory, soft tissue, urinary tract, bone or septicemic infections due to gram negative bacilli. Median sensitivity to tobramycin of Pseudomonas aeruginosa isolates (19 strains) was 0.62 mug/ml and range 0.31-2.5 mug/ml; less activity was observed for Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae and Enterobacter species isolates but median minimum inhibitory concentrations were less than or equal to 2.5 mug/ml. Therapy resulted in clinical and bacteriologic cures in 16 patients (53 per cent) including 13 of 16 (181 per cent) with urinary tract infections; 9 of the 14 patients who did not obtain bacteriologic cure had satisfactory clinical responses. Tobramycin was effective for selected gram negative bacillary infections and particularly for P. aeruginosa.

Tobramycin: a review of its antibacterial and pharmacokinetic properties and therapeutic use.

SYNOPSIS: Tobramycin is a new aminoglycoside antibiotic with a broad antibacterial spectrum in vitro, and pharmacokinetic properties similar to those for gentamicin. Tobramycin is more active than gentamicin against Pseudomonas aeruginosa and active against many gentamicin resistant strains, but is not active against enterobacteriaceae resistant to gentamicin. Theoretically, tobramycin has an advantage over gentamicin against infections caused by P. aeruginosa, but any advantage in clinical practice has yet to be adequately demonstrated. Clinical experience with tobramycin is considerably less than with gentamicin. Whilst tobramycin appears to offer no clear advantages over gentamicin against sensitive organisms it is indicated in infection caused by strains of P. aeruginosa which are resistant to gentamicin, but sensitive to tobramycin. Like gentamicin, tobramycin acts synergistically with corbenicillin and the cephalosporins. The efficacy of the tobramycin-carbenicillin combination has been shown in endocarditis caused by P. aeruginosa which was unresponsive to gentamicin plus carbenicillin. Ototoxicity and nephrotoxicity similar to that seen with other animoglycosides have been encountered in therapeutic trials with tobramycin and wider clinical experience is necessary to determine the relative incidence of these side-effects with gentamicin and tobramycin used under similar conditions. Antimicrobial activity: In comparative studies, in vitro, tobramycin is more active than gentamicin against clinical isolates of Pseudomonas aeruginosa. Similarly, the inhibitory index, which is the ratio between the serum concentration attained at usual therapuetic doses and the minimum inhibitory concentration, for Pseudomonas aeruginosa is higher for tobramycin than for gentamicin. Against Gram-negative bacteria other than Pseudomonas spp. the spectrum of activity of tobramycin is similar to that of gentamicin. For most species the activity of tobramycin is slightly less than that of gentamicin. Gentamicin is consistently more active than tobramycin against Serratia marcescens. Like other aminoglycoside antibiotics, tobramycin is active in vitro in low concentrations against Staphylococcus aureus. Tobramycin is essentially inactive against Streptococcus pyogenes, Streptococcus faecalis and Streptococcus pneumoniae (pneumococci). Maner aminoglycosides and of other antibiotics against various bacteria in vitro, but comparisons between studies cannot always be interpreted literally because the activity of many antibiotics in vitro, including tobramycin, is influenced by the nature of the culture media and the presence of certain salts. The sensitivity of P. aeruginosa to tobramycin is influenced by the magnesium, and calcium content of the culture media whilst that of all species is reduced by sodium ions. Wide variations in the concentration of these ions may result in divergent MIC values and an inappropriate choice of antibacterial agent to treat pseudomonas infection...