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Tobramycin remains the anchor drug for bacterial keratitis treatment and management; however, unlike other aminoglycosides, it does not pass through the gastrointestinal tract. The aim of the current investigation was to formulate tobramycin-loaded nanostructured liquid crystalline particles as an ophthalmic drug delivery system to ameliorate its preocular residence duration and ophthalmic bioavailability. Tobramycin cubosomes were fabricated by liquid–lipid monoolein, water, and poloxamer 407 as a stabilizer. Corneal penetration studies exhibited that the apparent permeation coefficient of tobramycin cubosomes was nearly 3.6-fold greater than marketed tobramycin eye drops. Ocular in vivo analysis performed in rabbits' eyes manifested that the intensity of bacterial keratitis was reduced on day 3, and on day 5, the manifestations were considerably mitigated with tobramycin cubosomes as compared to marked eye drops. Pharmacokinetic study of rabbit aqueous humor demonstrated that the area under curve and the peak concentration of optimized cubosomes were 3.1-fold and 3.3-fold, respectively, which was significantly higher than marketed eye drops. Moreover, histopathological studies illustrated the existence of normal ocular structures, thus indicating that there was no damage to the corneal epithelium or stromal layer. Consequently, the results acquired demonstrated that tobramycin-loaded cubosomal formulation could be a propitious lipid-based nanodelivery system that would enhance retention time and corneal permeability contrast to commercial eye drops.

Conventional topical delivery in hyperacute bacterial conjunctivitis and endophthalmitis is associated with low drug bioavailability due to rapid precorneal clearance. Hence, in the present investigation, an attempt has been made to enhance ocular bioavailability of tobramycin sulfate by formulating drug-loaded microparticles dispersed in thermosensitive in situ gel.Microparticles prepared by emulsion-ionic gelation technique were characterized for drug loading, entrapment efficiency, particle size, surface morphology, and in vitro drug release. Consequently microparticles (F2 prepared with 1.5%w/v chitosan, 0.2%w/v tripolyphosphate, and drug, 30%w/w of polymer) with high drug loading and encapsulation efficiency were dispersed in thermosensitive in situ gel containing poloxamer 407 and varying percentage of chitosan. In situ gel containing drug-loaded microparticles were evaluated for gelation temperature, rheological behavior, mucoadhesive strength, in vitro drug release, in vitro permeation, ocular irritation, and bioavailability in aqueous humor of rabbits.Formulation containing 17%w/v poloxamer 407 and 0.5%w/v chitosan (P2) gelled at 32°C ± 1.5°C gave pseudoplastic behavior. In vitro permeability of tobramycin from the formulation P2 was found 2-folds greater than eye drops. It also gave significantly higher aqueous humor concentration of tobramycin compared with eye drops with no signs of ocular irritation.Thus, the formulation possesses high potential for treating ocular infections.

It is unknown if inactive pharmaceutical ingredients influence the activity of antibiotics they are co-formulated with. Recently it was found that materials acting as carbon nutrient sources for bacteria can promote bacterial dispersion from a biofilm and/or reverse the persister state of a subpopulation of bacteria within the biofilms. Both can make bacteria more susceptible to antibiotics. Thus, the aim was to identify potential excipients to improve antibiotic activity in Pseudomonas aeruginosa biofilms.We screened 190 potential excipients alone, and in combination with tobramycin sulfate against P. aeruginosa (strain PAO1) grown planktonically or as biofilms. After the excipient screening stage, we investigated the effect of 10 selected excipients against a more virulent strain (luminescent strain UCBPP-PA14). Temporal changes in luminescence, as an indicator of bacterial proliferation, and surviving colony forming units (CFUs) from the treated PA14 biofilms were quantified.Forty-eight materials tested caused a reduction of PAO1 proliferation either alone or combined with tobramycin. L-alanine (p 0.05), D-alanine (p 0.05), and N-acetyl-D-glucosaminitol (p 0.05) improved the activity of tobramycin measured by PA14 luminometry. Additionally, L-alanine and succinic acid significantly reduced the survival of PA14 biofilms (p 0.05).L-alanine, succinic acid, and N-acetyl-D-glucosaminitol may be useful as antibiotic adjuvants in future tobramycin anti-biofilm formulations.

Chronic infections with Pseudomonas aeruginosa are a leading cause of morbidity in patients with cystic fibrosis (CF). The aim of tobramycin inhalation therapy in CF patients with chronic pulmonary infection is to deliver high amounts of drug directly to the site of infection. TOBI(®) is a tobramycin nebulizer solution (300 mg/5 ml) approved by FDA for maintenance therapy for patient with CF. The 20% tobramycin sulfate solution was reported as the optimal and maximal concentration.Nebulization of high strength tobramycin solution (20% tobramycin sulfate) (HSTS) has been assessed in this study by using different selected high performance nebulizer delivery systems: two different designs of jet nebulizers, and three new nebulizers based on vibrating mesh technology. The aerosol particle size distribution and output characteristics were measured for in vitro performance assessment of the nebulizer systems. The methodology was adapted from the current European standard, EN 13544-1:2001E.The particle size distribution characteristic measurements showed that all tested nebulizers may be suitable for inhalation of HSTS. The mean (SD) of highest percentage of fine particles (5 μm) was 77.64 (2.3) % for Sidestream(®), at flow rate 16 L/min. The highest respirable inhaled mass was for Pari LC Plus(®) combined with PariBoyN(®) compressor, with mean (SD) 90.85 (8.6) mg. The mean (SD) of highest drug wastage percentage was 63.9 (3.9) % for Sidestream(®) jet nebulizer combined with compressed air cylinder at flow rate 16 L/min, while the lowest was 2.3 (0.26) % for NE-U22 Omron(®) (high frequency).The HSTS can be nebulized by all tested nebulisers but the high frequency NE-U22 Omron(®) and Aeroneb Go(®) are more efficient. When the HSTS compared to TOBI(®), the respirable inhaled dose was increased to more than 73%.

In a weak acidic medium, the reaction of some aminoglycoside antibiotics (AGs) such as kanamycin sulfate (KANA), gentamycin sulfate (GEN), and tobramycin sulfate (TOB) with acid thiazolyl bisazo dye Titan Yellow (TY) can result in the fading of TY. The maximum fading wavelength was located at 409 nm. The molar absorptivities (ɛ/×104 1 mol−1 cm−1) were 2.0, 1.5 and 2.5 for KANA, GEN and TOB, respectively. The spectral characteristics, effect factors, optimum conditions of the reaction and the influence of foreign substances were also investigated. The procedure is easy and fast. This method has high sensitivity and can be applied to the determination of commercial aminoglycoside antibiotics and serum samples with satisfactory results.

Calcium sulfate was used as a biodegradable delivery system for the administration of antibiotics in musculoskeletal infection. New Zealand white rabbits were infected with Staplylococcus aureus, debrided, and randomized to one of four treatment groups: calcium sulfate pellets with 10% tobramycin sulfate, placebo calcium sulfate pellets and IM tobramycin, placebo calcium sulfate pellets, or debridement. Serum and wound exudate tobramycin concentrations and serum calcium levels were measured. Radiographs, cultures, and histology were analyzed for efficacy and treatment. Rabbits treated with 10% tobramycin sulfate pellets showed a significantly higher eradication of infection (11/13) than rabbits treated with debridement only (5/12), placebo pellets and IM tobramycin (5/14). or placebo pellets (3/13). In the group receiving 10% tobramycin sulfate pellets, serum tobramycin concentrations peaked 3 h post-operatively at 5.87 microg/ml and were non-detectable after day 1. In the group receiving placebo pellets and IM tobramycin, serum concentrations peaked at 7.82 microg/ml 1 h post-operatively, fell to 6.12 microg/ml on day 2, and averaged 4.18 microg/ ml for the remainder of the treatment period. The wound exudate tobramycin concentrations in the animals treated with tobramycin sulfate pellets peaked at 11.9 mg/ml on day 1 and dropped to 2.5 microg/ml on day 7. There was no significant difference in the serum calcium levels in any of the treatment groups. Calcium sulfate containing tobramycin sulfate has potential utility as a biodegradable local antibiotic delivery system in the treatment of musculoskeletal infections.

The aims of the present study were to determine the disposition of tobramycin after single intravenous (IV) and intramuscular (IM) injections in ducks, and to establish any sex-related differences. Tobramycin sulfate was administered as a 2.5% water solution in a cross-over design at a dose of 5mg/kg to 12 healthy ducks (six males and six females). Concentrations of the drug in serum were determined by a microbiological assay. The serum pharmacokinetic values for tobramycin were best represented using a one- or two-compartment open model, depending on the method of administration. Non-compartment analysis was also performed after IV administration. Tobramycin had a low degree of distribution and a relatively fast elimination. The mean volume of distribution in ducks (males and females) was higher than that reported in pigeons but lower than in chickens, with a slower rate of elimination. The IM injection resulted in a fast and complete absorption. The rate of elimination after IM administration was about twice as slow as in other avian species. Sex-related variations in tobramycin pharmacokinetics were similar to those reported for kanamycin and apramycin in hens and roosters.

Purpose: To study the compatibility of combinations of antibiotics and steroids commonly used in anterior segment surgery. Setting: Research Laboratory, Helsinki University, Finland. Methods: Aggregate production in vitro and in vivo was studied for three injectable antibiotics (cefotaxime sodium, tobramycin sulfate, and gentamicin) and four corticosteroids (triamcinolone acetonide, methylprednisolone sodium succinate, methylprednisolone acetate, and dexamethasone sodium phosphate) using conventional and dark-field microscopy. Aggregate formation on collagen shields and subconjunctival aggregate formation of tobramycin sulfate in combination with methylprednisolone acetate or dexamethasone sodium phosphate was also studied. Results: Dexamethasone sodium phosphate (4 mg/mL) did not form aggregates with any of the three antibiotics tested. Cefotaxime sodium did not cause aggregates when 24 mg/mL of dexamethasone sodium phosphate was used both in vitro and in vivo or in association with collagen shields. Conclusions: To avoid undesired side effects, such as epithelial sloughing and corneal edema after collagen shield application, antibiotics and steroids must be carefully selected.

Objective: To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h. Design: Randomized, controlled, crossover, prospective, open-label trial. Setting: Medical college-affiliated hospital. Participants: Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg. Interventions: Volunteers received, in random order, tobramycin sulfate 2 mg/kg iv on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast). Main Outcome Measures: Primary endpoints were area under the time–concentration curve (AUC), time to reach maximum concentration (tmax), and maximum concentration (Cmax). Secondary endpoints were elimination rate constant (ke), clearance (Cl), and half-life (t1/2). Results: Six volunteers successfully completed the trial. The tmax values observed following fast CRIS and ivpb were 28 ± 8 and 32 ± 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the tmax associated with slow CRIS (44 ± 7 min). The Cmax values observed following ivpb (11.2 ± 1.5 mg/L) and slow CRIS (10.9 ± 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 ± 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 ± 4.8 and 31.2 ± 3.8 mg/L•h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 ± 4.3 mg/L•h). No significant difference in ke (fast CRIS 0.32 ± 0.03 h-1; slow CRIS 0.33 ± 0.04 h-1; ivpb 0.34 ± 0.0 h-1) was observed among any of the methods. Conclusions: CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher Cmax, but the tmax values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed tmax, but the Cmax values of slow CRIS and ivpb were not statistically different.

This pilot study was undertaken to evaluate the short-term in vitro antimicrobial stability of both vancomycin- and tobramycin-impregnated calcium sulfate pellets mixed and stored in a clinical setting. Powdered tobramycin sulfate (500 mg) and vancomycin hydrochloride (500 mg) were blended into separate basins containing 25 g of surgical-grade calcium sulfate powder, then mixed with 8 mL of sterile saline. From this admixture, 6.0-mm pellets were produced. These were removed from the sterile container (stored at room temperature) at 1, 7, 30, 60, 90, and 120 days and tested against a variety of pathogenic bacterial isolates by using a modification of the standardized Kirby-Bauer test. Control pellets containing no antibiotic were also evaluated. There was no inhibition of bacterial growth by the non-antibiotic-impregnated (control) pellets. There was no appreciable difference in the zones of inhibition for any of the organisms with pellets stored for 1, 7, 30, 60, 90, or 120 days. Zones of inhibition for the various antibiotics to the strain of organism tested ranged from 17 mm to 30 mm, depending on the pathogenic isolate and the antibiotic evaluated. The zones of inhibition observed were similar to those designating antibiotic susceptibility in the Kirby-Bauer test. The results of this preliminary study suggest that clinician-mixed calcium sulfate pellets containing either vancomycin or tobramycin, when stored under normal room temperature and ambient humidity, appear to maintain their antimicrobial characteristics for at least 120 days.

The interactions of sucralfate with colistin sulfate, with tobramycin sulfate, and with amphotericin B were studied. Sucralfate 500 mg was added to 40 mL of distilled water adjusted to pH 3.5 with hydrochloric acid. Stock solution of one of the three antibiotics was added to give a final colistin concentration of 50 mg/L (as the sulfate salt), final tobramycin concentration of 50 mg/L (as the sulfate salt), and final amphotericin B concentration of 25 mg/L. Samples were removed from each sucralfate-antibiotic mixture at 0, 5, 10, 15, 30, 45, 60, and 90 minutes and analyzed for antibiotic concentration by high-performance liquid chromatography (colistin), enzyme immunoassay (tobramycin), and spectrophotometry (amphotericin B). To determine if any interaction was reversible, the mixtures were stored for 90 minutes without sampling, the pH was adjusted to 6.5-7.0, and samples were removed and analyzed. All tests were performed in triplicate, and the temperature was maintained at 25 degrees C. Significant drug loss was observed starting at five minutes for each antibiotic-sucralfate mixture. This effect was not reversible in the less acidic environment. The concentrations of colistin, tobramycin, and amphotericin B declined rapidly when each drug was combined separately with sucralfate.

The compatibility of ciprofloxacin injection with selected antimicrobials and aminophylline was studied. Ciprofloxacin, amikacin sulfate, aminophylline, clindamycin phosphate, gentamicin sulfate, and tobramycin sulfate were mixed separately in minibags containing 0.9% sodium chloride injection or 5% dextrose injection; admixtures were stored for up to 48 hours at either 4 degrees C or 25 degrees C. Ciprofloxacin was also combined separately with each of the other drugs and solutions and stored under the same conditions. In addition, ciprofloxacin was combined with metronidazole in ready-to-use mini-bags of the latter drug and stored at 25 degrees C. Drug concentrations were measured by fluorescence polarization immunoassay or high-performance liquid chromatography. All admixtures were also examined visually. Stability was defined as retention of at least 90% of the original drug concentration with no visual evidence of incompatibility. With one exception, drugs in all single-drug admixtures were stable for 48 hours. The drug concentration eight hours after amikacin was mixed in 0.9% sodium chloride and refrigerated was 89% of the original concentration. When ciprofloxacin was combined with gentamicin, metronidazole, or tobramycin, all of the involved drugs were stable for 48 hours. Compatibility of ciprofloxacin-amikacin admixtures depended on the fluid and storage temperature; all such admixtures were stable for at least eight hours. A precipitate formed immediately whenever ciprofloxacin was mixed with clindamycin and within four hours after ciprofloxacin was mixed with aminophylline. Ciprofloxacin injection was compatible with gentamicin, metronidazole, and tobramycin and incompatible with aminophylline and clindamycin. The compatibility of ciprofloxacin-amikacin admixtures depended on the i.v. solution and storage temperature.

We studied the potency of fortified ophthalmic antibiotic preparations of cefazolin sodium (50 mg/ml) and tobramycin sulfate (15 mg/ml), as measured by the minimum inhibitory concentration, against Streptococcus pneumoniae and Pseudomonas aeruginosa, respectively. We also examined absorbance spectra, pH, and the effect of storage temperature on these fortified solutions to determine their stability over a four-week period. Cefazolin and tobramycin maintained a constant potency throughout the experiment. There was no difference in potency if the fortified solutions were stored at 4 C or 24 C. Cefazolin stored at 24 C exhibited changes in both its absorbance spectra and pH after seven days. Cefazolin stored at 4 C and tobramycin stored at 24 C and 4 C remained stable throughout the four-week period.

The aims of this study were to (1) quantify the particle size characteristics of several antibiotics considered suitable for aerosol therapy after aerosolization with the PARI IS/2 nebulizer (Pari GmbH, Sarnberg, Germany) and (2) determine the degree to which in vitro antimicrobial activity of these antibiotics is maintained after nebulization. The aerosolized drugs were tobramycin sulfate, streptomycin, and imipenem, with saline solution as the control. Mean mass aerodynamic diameter of the nebulized drugs was 3.25 microns for tobramycin, 2.26 microns for imipenem, and 2.38 microns for streptomycin. In vitro tests showed that tobramycin and imipenem were unaltered in their bacteriostatic activity against strains of Escherichia coli (American Type Culture Collection [ATCC] 25922) and Staphylococcus aureus (ATCC 29213) as well as against Pseudomonas aeruginosa (ATCC 27853) with minimal inhibitory concentration (MIC) values less than 0.3 microgram/mL. Nebulized streptomycin showed significantly higher MIC values against P. aeruginosa (ATCC 27853). These results suggest that tobramycin and imipenem may be prescribed as an aerosol generated by jet nebulization (PARI IS/2) to treat S. aureus, E. coli, and P. aeruginosa infections without any risk of altering the drugs minimum bacteriostatic activity by the nebulization process. Aerosolization of streptomycin with this nebulizer may not be as effective against P. aeruginosa because it seems to alter the bacteriostatic activity.

The stability of gentamicin sulfate and tobramycin sulfate in fortified ophthalmic solutions stored under refrigeration was studied. Fortified gentamicin ophthalmic solution and fortified tobramycin ophthalmic solution were prepared to a final theoretical concentration of 13.6 mg/mL by using commercially available ophthalmic and injectable solutions. Volumes of each solution were packaged in plastic bottles and refrigerated at 4-8 degrees C. Samples of each solution were analyzed by fluorescence polarization immunoassay on days 0 (before refrigeration), 1, 2, 3, 4, 7, 14, 28, 63, and 91. To validate the method, identical solutions were prepared, stored under refrigeration at 4-8 degrees C, and analyzed by a stability-indicating high-performance liquid chromatographic assay on days 0 (before refrigeration), 9, 28, 56, and 91. Fluorescence polarization immunoassay showed the mean concentrations of gentamicin and tobramycin on day 91 to be 104.4% and 97.4%, respectively, of the time 0 concentrations; the difference was not significant in either case. HPLC validated these results; the mean concentration of gentamicin and tobramycin on day 91 was 103.3% and 101.2%, respectively, of the mean day 0 concentrations. Gentamicin and tobramycin in ophthalmic solutions prepared by mixing ophthalmic and injectable products and stored in plastic bottles at 4-8 degrees C were stable for three months.

• A total of 26 albino guinea pigs were treated with 200 mg/kg/day of tobramycin sulfate. Animals were killed at various intervals of up to three weeks after seven days treatment. Outer hair cell (OHC) loss of the organ of Corti was evaluated by surface preparation techniques, and glycogen was assessed with PATCO- and PAS-stained sections. We have concluded that permanent damage of OHCs is most prevalent in areas that normally have the least amount and the smallest granule size of glycogen. With treatment, these susceptible areas are the least responsive in terms of an early increase in glycogen production. Furthermore, by 21 days after seven days of treatment, these same areas will reveal an almost total loss of glycogen at a time when damage is maximal. ( Arch Otolaryngol 102:154-159, 1976)

Prescribing physicians at our institution were required to obtain approval from the Section of Infectious Disease for use of gentamicin sulfate and other aminoglycosides. We studied the effect of removing gentamicin from the list of restricted antibiotics, noting that gentamicin usage increased while tobramycin sulfate usage decreased during the six-month period after decontrol, compared with the previous six-month period. However, the total amount of aminoglycoside antibiotics procured by the pharmacy did not change significantly. Indications for aminoglycoside use, pretreatment evaluation of the patient (other than an initial serum creatinine determination), and rates of nephrotoxicity during treatment did not change. Decontrol of gentamicin resulted in lower aminoglycoside costs for the pharmacy without apparent compromise in patient care.

The elimination pharmacokinetics of tobramycin sulfate was studied in 25 newborn infants of birth weight 0.7 to 4.7 kg during 31 treatment episodes. The peak serum concentrations after a 2.5 mg/kg dose were usually within the therapeutic range of 5 to 10 micrograms/ml; however, the serum predose trough values were elevated above the theoretical safe limit of 2 micrograms/ml. Because of the prolonged serum elimination half-lives, a calculated extended dosage interval, sometimes greater than 24 hours, was necessary to obtain a predose trough of less than or equal to 2 micrograms/ml. The serum elimination half-lives inversely correlated with gestational age, extrauterine age, birth weight, and creatinine clearance. The very low ratio of tobramycin renal clearance to creatinine renal clearance was virtually constant and indicated a probable tubular reabsorption of tobramycin. A general dosage schedule based on birth weight was derived from the data. An alternative formula was derived to enable prediction of the tobramycin elimination half-life based on a combination of birth weight, gestational age, and extrauterine age for an infant younger than 7 days of age.

The effects of various formulation factors on the in vitro release characteristics of spherical polymethylmethacrylate implants were studied. Physical and mathematical models were proposed to describe observed in vitro release profiles. The in vitro release data could be described by a biexponential equation of the type: fraction of tobramycin remaining in the implant at time t = Ae−αt + Be−βt, where α and β represent the rate constants for the initial rapid and subsequent slow phases of release. The influence of drug loading, volume of dissolution medium, implant size, type of commercial cement and the incorporation of water soluble additives on the release profiles as well as the α and β rate constants is described

Collagen shields made of porcine collagen were placed in a solution containing tobramycin sulfate (40 or 200 mg/ml) for five minutes, then applied to rabbit eyes. One, four, or eight hours after application, the corneas, aqueous humor samples, and shields were assayed for antibiotic. At all intervals, the concentration of antibiotic in the corneas and aqueous humor samples exceeded the mean inhibitory concentration for tobramycin, as determined for most strains of Pseudomonas . Shields immersed in 200 mg/ml tobramycin produced significantly higher concentrations of antibiotic in the cornea at one hour than subconjunctival injections of tobramycin (20 mg) ( P .0001). Shields immersed in 40 mg/ml tobramycin produced higher, although not significantly higher, concentrations of antibiotic in the cornea at one hour than subconjunctival injections of tobramycin (20 mg) ( P = .318). Shields immersed in commercially available tobramycin drops or injectable tobramycin solution (40 mg/ml) caused no epithelial damage visible by slitlamp examination. Collagen shields containing antibiotics can serve as a vehicle for drug delivery and may prove superior to current methods for preoperative and postoperative antibiotic prophylaxis and the initial treatment of bacterial keratitis.

The effect of semistarvation on the toxicity and ototoxicity of tobramycin sulfate (TO) and gentamicin sulfate (GE) was investigated in guinea pigs by electrophysiological and histopathological methods. The presented data has shown that the toxicity and ototoxicity of aminoglycoside antibiotics is substantially increased when guinea pigs were semistarved. Our results should also warn researchers using semistarvation in their conditioning experiments which investigate the toxicity of different chemicals. Toxicity was greater in GE- than TO-treated animals, which caused the GE-treated animals to die during treatment or shortly after treatment. Thus, TO should be preferentially used because it has been shown to be less toxic and ototoxic in normal and altered nutritional conditions.

This study was designed to evaluate the serum concentration of tobramycin sulfate following a 2.5-mg/kg intravenous infusion in 43 premature infants on days 1, 3, and 5 of age (therapy). Twenty premature infants weighing 1500 gm or less at birth and 23 others whose birthweights ranged from 1501 to 2500 gm made up the study population. Serum tobramycin levels were measured by an enzymatic immunoassay (EMIT) at one, four to six, and 12 hours after injection. Peak serum levels increased from day 1 (means, 5.2 +/- 2.2 mcg/ml) to day 3 (means, 6.1 +/- 2.6 mg/ml) and then remained unchanged at day 5 (means, 6.1 +/- 2.4 mg/ml). Approximately 40% of the study population presented trough levels above 2 mcg/ml on day 1 and over 70% on days 3 and 5. No evidence of renal toxicity or auditory dysfunction was observed. In light of the high trough levels observed during the first week of life in premature infants, it may be judicious to monitor serum tobramycin concentration and to decrease the dosage or to prolong the dose interval in order to maintain trough concentrations below 2 mcg/ml.

The effectiveness of cryotherapy alone and in combination with topical tobramycin sulfate therapy for experimental Pseudomonas keratitis was determined in guinea pigs and rabbits. Results were evaluated quantitatively by determining numbers of viable bacteria surviving in corneas. A brass probe cooled to--79 degrees C and applied directly to infected corneas for six seconds resulted in an immediate 99.9% reduction in bacteria. One freeze-thaw cycle followed by topical tobramycin therapy was significantly more effective than tobramycin therapy alone in five of six strains tested. None of the corneas treated with tobramycin alone demonstrated no growth, whereas 24 of 42 of these infected corneas showed no growth after the combination treatment. We conclude that cryotherapy alone had a rapid bactericdal effect on experimental Pseudomonas keratitis and that it significantly potentiated topical antibiotic therapy for most strains.

The stability and physical compatibility of tobramycin sulfate in commonly used intravenous fluids were evaluated; in addition, pH values were obtained on 1 mg/ml tobramycin solutions, and microbiological potencies were obtained on 1 mg/ml and 0.2 mg/ml concentrations for 24- and 48-hour periods at 25 C. Most solutions were stable for 48 hours at room temperature. However, it is recommended that solutions of tobramycin sulfate be discarded after 24 hours to minimize the potential for inadvertent introduction of microorganisms during manipulations in the hospital environment.

A 14C-radiorespirometric assay was used to show the sensitivity of fixed-film (sessile), catheter-associated and free-living (planktonic) cells of Pseudomonas aeruginosa to varying concentrations (100 micrograms/mL to 1000 micrograms/mL) tobramycin sulfate. This strain of P. aeruginosa has an MIC of 0.6 microgram/ml and an MBC of 50 micrograms/mL when tested by conventional methods. When 14C-glutamic acid was used as a substrate in this radiorespirometric assay, it could be completed in less than one hour and planktonic samples showed a significant reduction in mineralization activity (evolution of 14CO2) within eight hours of the antibiotic challenge. These changes in respiratory activity appeared to be dose and time dependent. Within 18 hr. at 1000 micrograms/mL, there was no significant residual respiratory activity in planktonic samples. Some residual respiratory activity was detected, however, in samples exposed to 100 micrograms/mL for 36 hours. The mineralization activity of sessile catheter-associated bacteria was unaffected by four hr. and eight hr. exposures to 1000 micrograms/mL of the antibiotic. A significant reduction in respiratory activity was recorded in catheter samples exposed for 18 hr. or more at each concentration examined. Unlike the planktonic samples, however, the antibiotic challenge failed to eradicate the metabolic activity of the attached bacteria. Antibiotic stressed, catheter-associated bacteria transferred to a post-exposure enrichment broth showed a limited ability to re-establish respiratory activity. This apparent recovery was limited to antibiotic exposures less than 24 hr. and was not observed in planktonic samples. The radioisotopic assay is a non-culture method which can be used to assess the antibiotic sensitivity of both planktonic bacteria and "in situ" biofilm populations. Clinically, it can be used to demonstrate that some adherent biofilm bacteria can survive the exposure to antibiotics that is achieved in routine chemotherapy.

The stability of tobramycin in pooled human serum when combined with ampicillin, carbenicillin disodium, or penicillin G potassium after storage at 0, 23, or 37 degrees C was evaluated. Samples of pooled human serum containing tobramycin sulfate 8 micrograms/ml alone or combined with ampicillin, carbenicillin disodium, or penicillin G potassium 200 micrograms/ml were prepared and stored at 0, 23, and 37 degrees C. Single samples were removed periodically for 48 hours and frozen until assayed. Tobramycin concentration was measured by a radioenzymatic assay. A tobramycin degradation rate constant was calculated for the tobramycin control and each tobramycin-penicillin combination at each temperature; from this, the time for the tobramycin concentration to decline to 90% of the initial concentration (t90) was estimated. Stability of the penicillins was not assessed. Tobramycin degradation approximated a log-linear process in all samples for the 48-hour period. The tobramycin control sample was more stable than any of the tobramycin-penicillin solutions at each temperature. At 0 degrees C, tobramycin mixed with ampicillin was the least stable of all mixtures; at 23 and 37 degrees C, tobramycin mixed with carbenicillin was the least stable. Storing tobramycin and carbenicillin samples on ice (0 degrees C) prolonged t90 from 10 hours (23 degrees C) and 12 hours (37 degrees C) to 36 hours. The t90 values for tobramycin when mixed with ampicillin were 19, 16.5, and 20 hours at 0, 23, and 37 degrees C, respectively. Mixed with penicillin G, tobramycin t90 values at 0, 23, and 37 degrees C were 48, 44, and 16 hours, respectively. More than a 10% loss of tobramycin potency occurred in some tobramycin-penicillin solutions under the conditions of this study. Because this loss would affect the accuracy of tobramycin pharmacokinetic calculations, the authors suggested guidelines for handling tobramycin serum samples.

A hospital's use and costs of tobramycin sulfate versus gentamicin sulfate before and after a tobramycin use review were compared. Retrospective audits of 100 charts of adult patients in a 515-bed hospital were performed for two six-month periods in 1983-84. Tobramycin use was considered appropriate in patients with serum creatinine concentrations greater than 1.5 mg/dL or pre-existing renal disease, in any patient over 70 years of age, and in patients with neutropenia, documented pseudomonas infection, or infection with an organism shown to be resistant to gentamicin but sensitive to tobramycin. Tobramycin use was not justifiable in 37 (18.7%) of 198 patients whose charts were evaluable. Use of gentamicin in these 37 patients would have saved $14,300. The infection control committee was notified of the audit results; the audit results and recommendations for tobramycin use were included in a letter to all physicians; and the infectious disease service held educational conferences on tobramycin use. In the first six months after the corrective measures, mean monthly tobramycin use decreased by 38% and gentamicin use increased by 48.9%. Total aminoglycoside costs decreased 30.2% and total aminoglycoside use decreased 12.5%. In the second six months after intervention, mean monthly tobramycin use was 11% less than before intervention, and mean monthly gentamicin use was 13% greater than before intervention. Total aminoglycoside costs were 3.6% less and total aminoglycoside use was 4% less than before the audit. The tobramycin use audit and subsequent interventions with prescribers were effective in reducing tobramycin use and costs for approximately six months; decreases in tobramycin use and costs were smaller during the second six months after intervention.

The in vitro inactivation of tobramycin when combined with each of six cephalosporins in samples of human serum was investigated. Each of six cephalosporins (cefazolin sodium, cefoxitin sodium, cefamandole nafate, moxalactam disodium, cefoperazone sodium, and cefotaxime sodium) was added to human serum samples containing tobramycin sulfate 8 micrograms/mL to produce final cephalosporin concentrations of approximately 250 and 1000 micrograms/mL. Duplicate solutions were prepared and stored at either 0 or 21 degrees C. Solutions containing tobramycin 8 micrograms/mL alone and with carbenicillin disodium in four concentrations were prepared as controls. Samples were assayed using a fluorescence polarization immunoassay (TDX) at 0, 2, 4, 8, 12, 24, and 48 hours to determine tobramycin concentration; two of the carbenicillin-tobramycin solutions were frozen immediately for assay 53 hours later. Tobramycin concentrations in the admixtures were compared with those in tobramycin reference samples. At both temperatures, samples containing tobramycin with cefamandole 250 micrograms/mL or cefotaxime 250 micrograms/mL showed less than 10% inactivation of tobramycin for at least 48 hours. At 0 degrees C, tobramycin retained greater than 90% activity when combined with cefoperazone 250 and 1000 micrograms/mL. In samples containing cefazolin 250 micrograms/mL at 0 degrees C and cefoperazone 250 micrograms/mL at 21 degrees C, tobramycin was stable for 24 hours. Only samples containing moxalactam stored at 21 degrees C showed greater than 16% inactivation of tobramycin at 48 hours. Under these study conditions, tobramycin is only moderately inactivated in vitro when combined with clinically achievable concentrations of the tested cephalosporins (excluding moxalactam) and then stored for up to 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine if the presence of an in-line 0.22 μ cellulose ester membrane filter would hamper the delivery of a common adult dose of tobramycin sulfate. Solutions of tobramycin sulfate 80 mg in 100 ml D5W were assayed after 30 minute infusions through unfiltered and filtered administration sets; solutions post-flush of filtered sets were also assayed. Assay was done by Emit-QST. The results indicated that there was no significant difference in the delivery of tobramycin sulfate, regardless of the presence of an in-line filter. Solutions post-flush contained about ten percent of the drug, reflecting the amount in solution that remained in the tubing. Since ten percent can alter pharmacokinetic monitoring for patient dosing, a consistent procedure for flushing filtered administration sets should be adopted to enhance accuracy of such determinations.

An enzyme multiplied immunoassay technique (EMIT) and a microbiological assay were compared as methods for determining the concentration of tobramycin in human serum. Tobramycin sulfate in various concentrations (0.4-20.0 microgram/ml) was dissolved in lyophilized human serum. Tobramycin concentration was determined by EMIT assay and a microbiological agar diffusion assay using Bacillus subtilis ATCC 6633 as the test organism. Serum samples of 162 patients who received tobramycin 60 mg i.m. were also assayed by the two methods. The effect of six antibiotics on the determination of tobramycin concentration by EMIT assay was measured. To test whether freezing affects tobramycin concentration measured by EMIT assay, tobramycin in five concentrations in lyophilized human serum were frozen and analyzed at weekly intervals for seven weeks. The concentration of tobramycin determined by EMIT assay and microbiological assay in both lyophilized human serum and patient samples were highly correlated (r = 0.994 and 0.949) respectively). Dibekacin, an aminoglycoside structurally similar to tobramycin, interfered with the determination of tobramycin concentration. No effect of freezing was observed. The results of this study show that EMIT assay is an acceptable method for routine laboratory analysis of tobramycin serum concentration. It is as accurate as the microbiological assay tested.

• Iontophoresis of tobramycin sulfate was employed to treat bacterial keratitis induced in rabbits by an intrastromal injection ofPseudomonas aeruginosa. Quantitation of bacterial killing was achieved by culturing corneal homogenates and counting viable bacteria per cornea after treatment. When the rabbits received two iontophoretic treatments, iontophoresis significantly reduced the number of bacterial colony-forming units, compared with the use of an eyecup without current or two subconjunctival injections of 20 mg of tobramycin sulfate, and with untreated controls. The results of iontophoresis were not significantly different from those involving treatment with topical fortified drops (40 mg/mL). A single iontophoresis treatment was compared with the use of an eyecup without current or less fortified topical drops (13.6 mg/mL), as well as with untreated controls. Iontophoresis was significantly better than either the eyecup or the topical fortified tobramycin drops in reducing viable bacteria in the corneas. Iontophoresis may be a useful adjunct in the treatment of severe corneal bacterial infections.

The therapeutic efficacies of disodium ticarcillin, tobramycin sulfate, and N-formimidoyl thienamycin (MK0787) were compared in guinea pigs with experimentally induced Pseudomonas aeruginosa pneumonia. Survival rates were 35% for ticarcillin, 80% for tobramycin, and 75% for N-formimidoyl thienamycin. Numbers of viable Pseudomonas organisms in lungs approximately 3 h after the first dose of drug were nearly 10-fold fewer in tobramycin- or N-formimidoyl thienamycin-treated animals than in ticarcillin-treated animals. Our data suggest that N-formimidoyl thienamycin may have therapeutic efficacy against respiratory infections with P. aeruginosa equivalent to that of tobramycin.

Tobramycin sulfate, an aminoglycoside antibiotic, has been shown to be effective in the treatment of complicated urinary tract infections. Because of this, a study was undertaken to determine the penetrance of tobramycin into the prostate gland. It was found that the drug is concentrated at inhibitory levels in the prostate gland after the routinely recommended administration and should be useful in the treatment of bacterial prostatic infection.

Aminoglycoside therapy is routinely monitored at many institutions. It is widely known that serum concentrations of gentamicin and tobramycin may differ markedly among patients receiving the same doses of these drugs. One possible source of this variability may be interlot variation in the concentration of these drugs in commercial preparations. A study was designed to evaluate inter- and intralot variation in gentamicin and tobramycin concentrations at the labeled concentrations of 10 and 40 mg/ml. Multiple samples from six to 10 lots of commercially available gentamicin sulfate injection (Elkins-Sinn, Inc.) and tobramycin sulfate injection (Eli Lilly & Co.) were studied at each concentration. The actual percentage concentration of gentamicin in various lots ranged from 101 to 134% of the labeled concentrations; the actual percentage range was 101-109% at 10 mg/ml and 102-134% at 40 mg/ml labeled concentration. The actual percentage concentration of tobramycin in various lots ranged from 103 to 122% of labeled concentration; the actual percentage range was 107-117% at 10 mg/ml and 103-122% at 40 mg/ml labeled concentration. The intralot variation was less than 4% for both drugs at two concentrations. Based on these results, an 80-mg dose may in fact contain 107 mg of gentamicin or 98 mg of tobramycin. This may be clinically important in the care of patients and may at least in part explain the large variation in serum concentrations and difficulty in prediction of dosage requirements from routine monitoring. Furthermore, the available literature on pharmacokinetics, efficacy, and toxicity has not considered this interlot variation in aminoglycoside concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Peak and trough tear and serum concentrations were determined in 27 human volunteers undergoing intravenous (IV) gentamicin sulfate, tobramycin sulfate, amikacin sulfate, and netilmicin sulfate therapy. Although effective serum concentrations were achieved, tear levels were subtherapeutic. The mean peak tear concentrations were 0.4 microgram/mL, 0.5 microgram/mL, 1.7 micrograms/mL, and 0.3 microgram/mL for gentamicin, tobramycin, amikacin, and netilmicin, respectively. These levels did not approach the minimum inhibitory concentrations for Pseudomonas and raise some concern regarding the risk-benefit ratio of IV antibiotics for bacterial keratitis.

The penetration of tobramycin sulfate (nebramycin factor 6) into normal lower respiratory tract secretions was studied in a dog model. After a 1.7 mg/kg intravenous dose of tobramycin, the antibiotic was detected promptly in bronchial secretions, but the peak bronchial secretion concentration was not usually reached until 2 h after injection (mean level 1.15 μg/ml). The maximum tobramycin concentration in bronchial fluids was equal to the mean inhibitory concentrations that have been reported for about 80% of Pseudomonas isolates.

• To study the effectiveness of collagen shields containing tobramycin sulfate in the treatment of Pseudomonas keratitis, rabbits were infected via an intrastromal injection of Pseudomonas aeruginosa and treated 22 hours later with either collagen corneal shields rehydrated in 4% tobramycin and applied to the cornea or 4% tobramycin drops. Bacterial killing was quantitated by culturing corneal homogenates and calculating the number of viable bacteria (colony-forming units) per cornea. Corneas receiving shields rehydrated in 4% tobramycin and applied for four hours demonstrated significantly reduced numbers of bacteria compared with untreated control corneas. The collagen shields were as effective in reducing the number of viable bacteria per cornea as 4% tobramycin drops applied every 30 minutes over a four-hour period. Over a nine-hour treatment period, the addition of four drops of 4% tobramycin to shields in situ was as effective as exchange with a new shield rehydrated in 4% tobramycin. These results suggest that collagen shields rehydrated in a water-soluble antibiotic such as tobramycin may be an effective and convenient mode of therapy for Pseudomonas keratitis.

The ototoxicities of tobramycin sulfate and gentamicin sulfate were investigated in guinea pigs under conditions of normal, increased, and decreased hydration. Increased hydration was associated with no decline in the amplitude of the cochlear microphonics, a lesser decline in the eighth nerve action potentials and lesser damage to the organ of Corti. Decreased hydration was associated with an increase in the threshold of the cochlear microphonics and the eighth nerve action potentials, a decline in the amplitude of the cochlear microphonics, a greater decline in the eighth nerve action potentials, and greater damage to the organ of Corti. Tobramycin sulfate was substantially less toxic than gentamicin sulfate with normal, increased and decreased hydration. These findings suggest the preferential use of tobramycin sulfate for patients with normal renal function, and especially patients with renal impairment.

• Two cases of osteolytic lesion of the sternum were caused byPseudomonas aeruginosa. Both were in heroin addicts, and both occurred as a delayed reaction to injury in an automobile accident. Bony curettage and appropriate antibiotic therapy were sufficient for diagnosis and cure. Tobramycin sulfate (3 mg/kg/day), a new aminoglycoside, was successfully used in both instances. Excision of the sternum was not necessary. (Arch Surg111:776-778, 1976)

• A prospective randomized study compared the use of moxalactam disodium vs clindamycin phosphate and tobramycin sulfate for treatment of 190 patients with penetrating abdominal trauma. Twenty-seven patients were disqualified because of early death or failure to follow the protocol. The patients in each group were comparable regarding the cause and severity of injury. No significant difference was seen in the incidence of intra-abdominal infection between the moxalactam-treated group (13%) and the clindamycin- and tobramycin-treated group (9%). The intra-abdominal infection rate in patients with colon injuries (21%) was significantly increased when compared with the patients without colon injuries (6%), but the antibiotic regimen did not significantly change the infection rate. No evidence of bleeding problems from moxalactam were noted. Changes in prothrombin and partial thromboplastin times appeared to be related to shock rather than the use of moxalactam. The most severe coagulopathies occurred prior to moxalactam therapy and were seen only in those patients who had shock requiring 10 or more units of blood. Moxalactam is as effective as combination (clindamycin and tobramycin) antimicrobial therapy in patients with penetrating abdominal trauma. { Arch Surg 1986;121:153-156)

Fifty-four healthy guinea pigs were studied histologically for evaluation of Tobramycin sulfate ototoxicity. They were treated with 50, 100, 150 and 200 mg/kg/day under different schedules. Loss of hair cells occurred when dosage of 1,200 mg/kg was reached. Animals receiving 700 mg/kg were without damage to the inner ear. Outer hair cell loss occurred first in the basal turn, spreading upward. Inner hair cell loss began in the apical turn, progressing downward. When a total dose of 1,400 mg/kg was reached by (two) different schedules the higher daily dose produced about twice the hair cell loss; therefore, the ototoxic effect depends on the total dose but even more on the increased blood concentration.

A study of intravitreal injection of tobramycin sulfate in the treatment of experimental Pseudomonas aeruginosa endophthalmitis in rabbits resulted in the following findings: (1) A dose of 750 μg per 0.1 ml was nontoxic to ocular structures. (2) 500 μg of tobramycin sulfate remained bactericidal in both aqueous and vitreous humors for at least 96 hours. (3) Eyes cleared if treated with intravitreal injection of 500 μg tobramycin sulfate seven hours after bacterial inoculation, while only 2 of 5 eyes treated ten hours after inoculation showed complete clearing. (4) Systemic and subconjunctival administration of antibiotic failed to eradicate infection in 10 eyes.

• Antibiotic therapy of experimental Pseudomonas keratitis was evaluated quantitatively by determining numbers of viable bacteria in the cornea of guinea pigs. Topically applied carbenicillin disodium, gentamicin sulfate, and tobramycin sulfate were often significantly more effective than topically applied polymyxin B sulfate. Intramuscular therapy with tobramycin was as effective as topical therapy, and the results exhibited less variability. Topical tobramycin every 30 minutes was significantly more effective than topical therapy every 60 minutes. No combination of antibiotics was significantly better than a single effective drug. The concentration of tobramycin in the aqueous correlated more closely to therapeutic efficacy than did the concentration in the cornea. Although all antibiotics reduced numbers of bacteria in the cornea by more than 99% in the first 24 hours of therapy, none was able to sterilize the cornea in four additional days of continuous therapy. Persistence of organisms despite apparently adequate topical therapy may explain some reported cases of relapse in humans. ( Arch Ophthalmol 95:1638-1643, 1977)

The stability and compatibility of clindamycin phosphate admixed separately with gentamicin sulfate, tobramycin sulfate, and amikacin sulfate in polypropylene syringes under specific storage conditions were studied. In duplicate syringes, clindamycin phosphate 900 mg was admixed with sterile NaCl 0.9% 1 ml and with either gentamicin sulfate 120 mg, tobramycin sulfate 120 mg, or amikacin sulfate 750 mg. In duplicate polypropylene syringes, control solutions of clindamycin phosphate and each aminoglycoside were prepared separately and stored under the same conditions. The clindamycin control consisted of clindamycin phosphate 900 mg in 6 ml. The gentamicin and tobramycin controls consisted of gentamicin sulfate and tobramycin sulfate 120 mg in 3 ml plus 1 ml of sterile NaCl 0.9%. The amikacin control consisted of amikacin sulfate 750 mg in 3 ml plus 1 ml of sterile NaCl 0.9%. Drug concentrations were determined at the time of preparation and 1, 4, 8, 12, 24, and 48 hours thereafter. Aminoglycosides were assayed by fluorescence polarization immunoassay and clindamycin was assayed by high performance liquid chromatography. Visual inspections and pH determinations of each combination and control solution were performed at each assay time. For the clindamycin, gentamicin, tobramycin, and amikacin control solutions, changes in concentration were within ten percent of the original concentration. Concentrations of clindamycin and gentamicin when admixed together also remained within ten percent of the original concentration. Similar results were found with concentrations of clindamycin and amikacin when admixed together. Tobramycin and clindamycin formed a lasting precipitate upon initial contact when admixed under the study conditions.

Tobramycin sulfate, a new bactericidal aminoglycoside antibiotic, has been evaluated in 3,506 patients. Its in vitro activity is similar to that of other aminoglycoside antibiotics, except that it is more active against Pseudomonas aeruginosa. Clincal studies have shown that tobramycin sulfate is well tolerated and effective in the treatment of the infections listed below when they are caused by susceptible gram-negative organisms and by staphylococci: infections of the respiratory tract (including cystic fibrosis), central nervous system, skin, soft tissue, and bone (including burns); urinary tract and intraabdominal infections; and septicemia. The overall response was satisfactory in greater than 86% of the patients. Drug-related adverse effects were reported in 3.9% of the patients, and included reactions in the nervous system in 0.6% and in the kidney in 1.5%.

We evaluated several therapeutic modifications in an attempt to improve efficacy of topical therapy with tobramycin of experimental Pseudomonas keratitis in guinea pigs. Removal of corneal epithelium enhanced efficacy of topical therapy with 0.3 mg/ml and 3 mg/ml tobramycin sulfate but did not influence therapy with 40 mg/ml or 400 mg/ml tobramycin. The highest concentration of antibiotic was the most effective; 7 of 12 infected corneas treated with 400 mg/ml tobramycin were sterile in 48 hours. Therapy begun soon after the infection was established, when there were relatively few organisms present, was more effective than therapy begun later, when there were many more bacteria in the cornea. Our results are consistent with a basic therapeutic concept. The most effective regimen is one that achieves the highest safe concentration of antibiotic at the site of infection as early in the course of infection as possible.