Courses Of Tobramycin Research Articles

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis

BackgroundAminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF. MethodsCumulative AUCs were estimated for each course of tobramycin, for the 106 individuals with CF (between 4 and 22 years of age) enrolled in this retrospective study (35 who had received IV tobramycin, 71 controls). Mean hearing loss was calculated for each audiogram and a statistical model was developed to predict hearing loss. ResultsThe model confirms a significant relationship between cumulative tobramycin exposure and changes in hearing acuity:Meanhearingloss=2.7+(3×10−5)×AUC_tobramycin+individual_susceptibilityHowever, the ototoxic effect is not clinically perceptible (mean hearing loss: 3.8 dB). The impact of AUC on hearing loss is minor in these subjects who received a limited number of courses of tobramycin (median: 5 courses). ConclusionA significant relationship between cumulative exposure to tobramycin and ototoxicity was demonstrated. Individual treatment susceptibility should not be overlooked. As ototoxicity is not clinically perceptible in the study subjects, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss.

Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis.

Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.

Assessment of Detectable Serum Tobramycin Concentrations in Patients Receiving Inhaled Tobramycin for Ventilator-Associated Pneumonia.

Inhaled tobramycin can be used for empiric or definitive therapy of ventilator-associated pneumonia (VAP) in mechanically ventilated patients. This is believed to minimize systemic exposure and potential adverse drug toxicities including acute kidney injury (AKI). However, detectable serum tobramycin concentrations have been reported after inhaled tobramycin therapy with AKI. This retrospective, observational study evaluated mechanically ventilated adult subjects admitted to ICUs at a large, urban academic medical center that received empiric inhaled tobramycin for VAP. Subjects were separated into detectable (ie, ≥ 0.6 mg/L) or undetectable serum tobramycin concentration groups, and characteristics were compared. Independent predictors for detectable serum tobramycin concentration and new onset AKI during or within 48 h of therapy discontinuation were assessed. Fifty-nine inhaled tobramycin courses in 53 subjects were included in the analysis, of which 39 (66.1%) courses administered to 35 (66.0%) subjects had detectable serum tobramycin concentrations. Subjects with detectable serum tobramycin concentrations were older (57.1 y ± 11.4 vs 45.9 ±15.0, P = .004), had higher PEEP (9.2 cm H2O [7.0-11.0] vs 8.0 [5.6-8.9], P = .049), chronic kidney disease stage ≥ 2 (10 [29.4%] vs 0 [0%], P = .009), and higher serum creatinine before inhaled tobramycin therapy (1.26 mg/dL [0.84-2.18] vs 0.76 [0.47-1.28], P = .004). Age (odds ratio 1.09 [95% CI 1.02-1.16], P = .009) and PEEP (odds ratio 1.47 [95% CI 1.08-2.0], P =.01) were independent predictors for detectable serum tobramycin concentration. Thirty-seven subjects had no previous renal disease or injury, of which 9 (24.3%) developed an AKI. Sequential Organ Failure Assessment score (odds ratio 1.72 [95% CI 1.07-2.76], P = .03) was the only independent predictor for AKI. Detectable serum tobramycin concentrations were frequently observed in critically ill, mechanically ventilated subjects receiving empiric inhaled tobramycin for VAP. Subject age and PEEP were independent predictors for detectable serum tobramycin concentration. Serum monitoring and empiric dose reductions should be considered in older patients and those requiring higher PEEP.

Pharmacokinetic modelling to predict risk of ototoxicity with intravenous tobramycin treatment in cystic fibrosis.

Further optimization of therapeutic drug monitoring (TDM) for aminoglycosides (AGs) is urgently needed, especially in special populations such as those with cystic fibrosis (CF), >50% of whom develop ototoxicity if treated with multiple courses of IV AGs. This study aimed to empirically test a pharmacokinetic (PK) model using Bayesian estimation of drug exposure in the deeper body tissues to determine feasibility for prediction of ototoxicity. IV doses (n = 3645) of tobramycin and vancomycin were documented with precise timing from 38 patients with CF (aged 8-21 years), including total doses given and total exposure (cumulative AUC). Concentration results were obtained at 3 and 10 h for the central (C1) compartment. These variables were used in Bayesian estimation to predict trough levels in the secondary tissue compartments (C2 trough) and maximum concentrations (C2max). The C1 and C2 measures were then correlated with hearing levels in the extended high-frequency range. Patients with more severe hearing loss were older and had a higher number of tobramycin C2max concentrations >2 mg/L than patients with normal or lesser degrees of hearing loss. These two factors together significantly predicted average high-frequency hearing level (r = 0.618, P < 0.001). Traditional metrics such as C1 trough concentrations were not predictive. The relative risk for hearing loss was 5.8 times greater with six or more tobramycin courses that exceeded C2max concentrations of 3 mg/L or higher, with sensitivity of 83% and specificity of 86%. Advanced PK model-informed analysis predicted ototoxicity risk in patients with CF treated with tobramycin and demonstrated high test prediction.

Bayesian Forecasting for Intravenous Tobramycin Dosing in Adults With Cystic Fibrosis Using One Versus Two Serum Concentrations in a Dosing Interval.

Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration-time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice. Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively. A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L-1 and rRMSE of <15% for sequential c1 and c2 conditions. Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2-6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.

Optimizing Estimated Glomerular Filtration Rate to Support Adult to Pediatric Pharmacokinetic Bridging Studies in Patients with Cystic Fibrosis.

The estimated glomerular filtration rate (eGFR) is often used to model drug clearance (CL) and scale doses across age and body size. Over their lifetime, patients with cystic fibrosis (CF) receive repeated courses of tobramycin, an antibiotic with eGFR-dependent CL, for the treatment of pulmonary exacerbations. Tobramycin population pharmacokinetic (PK) modeling can be used to decipher the best approach to define eGFR for pediatric bridging studies. Inpatients with CF who received intravenous tobramycin between 1 January 2006 and 30 May 2018 were eligible for inclusion. Encounters without tobramycin concentration measurement or missing covariate data were excluded. Population PK analysis was performed using NONMEM.Covariate models were built following identification of the base model, with specific emphasis on the effect of different methods of estimating renal function as a covariate of tobramycin CL. A total of 296 CF patients contributed 1029 care encounters (420 pediatric, 609 adult) and 4352 tobramycin concentrations to this analysis. The median (minimum, maximum) age at encounter was 19years (0.2, 60), with serum creatinine of 0.60mg/dL (0.10, 3.41). A two-compartment model best described the observed data, with height and eGFR as significant covariates of tobramycin CL. eGFR was best modeled using a combination of the modified Schwartz and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equations expressed in absolute units. The CKDEPI equation bridges PK data generated in adults to adolescents with CF better than the current regulatory standard. The eGFR should be expressed in absolute units (mL/min) for PK analyses.

Glomerular and Tubular Renal Function after Repeated Once-Daily Tobramycin Courses in Cystic Fibrosis Patients.

Introduction. Antibiotic treatment regimens against Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients often include aminoglycoside antibiotics that may cause chronic renal failure after repeated courses. Aminoaciduria is an early marker of acute aminoglycoside-induced renal tubular dysfunction. We hypothesized that urinary amino acid reabsorption is decreased after repeated once-daily tobramycin therapies. Methods. In this prospective cross-sectional study creatinine clearance was estimated by the Schwartz and the Cockcroft-Gault formula. Tubular amino acid reabsorption was determined by ion exchange chromatography in 46 patients with CF who received multiple tobramycin courses (6.3 ± 10.1 (1–57)) in a once-daily dosing regimen and 10 who did not. Results. Estimated creatinine clearance employing the Cockcroft-Gault was mildly reduced in 17/46 (37%) of the patients who received tobramycin and 5/10 (50%) of the patients who did not but in none using the Schwartz formula. No association with lifetime tobramycin courses was found. Tubular amino acid reabsorption was not influenced by the amount of once-daily tobramycin courses. Conclusion. Clinically not significant reduction of eCCL occurred in a minority of CF patients. However, chronic tubular dysfunction was not present in patients with CF repeatedly treated with tobramycin in the once-daily dosing scheme.

Urinary kidney injury biomarkers and tobramycin clearance among children and young adults with cystic fibrosis: a population pharmacokinetic analysis.

Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF). Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing. We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1 (KIM-1). This was a prospective, observational cohort study of children/young adults with CF receiving once-daily intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children's Hospital Medical Center. Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Thirty-seven patients (median age 15.3 years, IQR 12.7-19.5) received 62 tobramycin courses. A one-compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best described the data. Urinary NGAL was associated with tobramycin CL (P < 0.001), as was urinary RBP (P < 0.001). SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharmacokinetic parameter estimates were CL = 8.60 L/h/70 kg (relative standard error 4.3%) and V = 31.3 L/70 kg (relative standard error 4.7%). We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individualize tobramycin therapy in patients with CF.

The pharmacokinetics and toxicity of morning vs. evening tobramycin dosing for pulmonary exacerbations of cystic fibrosis: A randomised comparison

BackgroundCircadian variation in renal toxicity of aminoglycosides has been demonstrated in animal and human studies. People with CF are frequently prescribed aminoglycosides. Altered pharmacokinetics of aminoglycosides are predictive of toxicity. AimTo investigate whether the time of day of aminoglycoside administration modulates renal excretion of tobramycin and toxicity in children with CF. To determine whether circadian rhythms are disrupted in children with CF during hospital admission. MethodsChildren (age 5–18years) with CF scheduled for tobramycin therapy were randomly allocated to receive tobramycin at 0800 or 2000h. Serum tobramycin levels were drawn at 1h and between 3.5 and 5h post-infusion between days 5 and 9 of therapy. Melatonin levels were measured serially at intervals from 1800h in the evening until 1200h on the next day. Circadian rhythm was categorised as normal when dim light melatonin onset was demonstrated between 1800 and 2200h and/or peak melatonin levels were observed during the night. Weight and spirometry were measured at the start and end of the therapy. Urinary biomarkers of kidney toxicity (KIM1, NAG, NGAL, IL-18 and CysC) were assayed at the start and end of the course of tobramycin. ResultsEighteen children were recruited to the study. There were no differences in renal clearance between the morning and evening groups. The increase in urinary KIM-1 was greater in the evening dosage group compared to the morning group (mean difference, 0.73ng/mg; 95% CI, 0.14 to 1.32; p=0.018). There were no differences in the other urinary biomarkers. There was normal circadian rhythm in 7/11 participants (64%). ConclusionsRenal elimination of tobramycin was not affected by the time of day of administration. Urinary KIM-1 raises the possibility of greater nephrotoxicity with evening administration. Four children showed disturbed circadian rhythm and high melatonin levels (ClinicalTrials.gov NCT01207245).

69 Efficacy on lung function and safety of multiple courses of tobramycin 300mg/4mL nebuliser solution (Bramitob) in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection: results from a 48-week extension phase

Objectives: Chronic treatment with inhaled antibiotics is part of the treatment regimen for cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa. Previously available treatments included nebulized antibiotics, but use of available preparations could be burdensome for patients and families. Two “newgeneration” formulations recently become available in Canada. We describe early experiences with Tobramycin Inhalation Powder (TIP, TOBI® Podhaler®) in a large pediatric CF centre. Methods: Patients who had initiated therapy with TIP were identified by retrospective chart review and demographic information was recorded (patient age, sex, CFTR mutation, culture results over 12 months, and treatment before starting TIP). Patients who ceased using TIP were identified. Data: TIP first became commercially available in Canada in April 2011. There are 170 patients between the ages of 6−18 years enrolled in the CHU-Sainte Justine clinic. As of January 2012, 32 patients had started therapy with TIP (mean age: 13.4 years (range 6−18 years, SD = 3.1 years), 14 females/18 males. 22 DF508 homozygous, 7 others with one DF508 allele). All were chronically colonized with P. aeruginosa; 31 also had other organisms. Before TIP, 12 were treated with TOBI®, 8 tobramycin, 9 colymycin, 1 tobramycin + colymycin, and 2 untreated. Three patients stopped therapy: 1 due to poor Podhaler technique, 1 bronchospasm, and 1 negative cultures for P. aeruginosa for 1 year. Conclusion: Early clinical experience with TIP in our centre has been positive, with initiation of therapy in 32 patients to date. Only 3 have stopped therapy, 2 due to factors associated with TIP.

Review of tobramycin levels in paediatric cystic fibrosis patients at Birmingham Children's Hospital

ObjectiveCystic fibrosis (CF) is a common recessive disorder with the lungs one of the primary organs affected. Many patients experience chronic pulmonary infection by Pseudomonas aeruginosa. Tobramycin, an aminoglycoside is...

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

Conclusion: Our results indicate that repeated treatment courses with tobramycin 10 mg/kg (twice daily for 3 weeks) may be safely applied in cystic fibrosis (CF) patients with respect to ototoxicity. The risk of hearing loss in this patient group is less than expected, which could be explained by either unfavourable baseline audiometry or the use of unidentified protective medication, or both. However, due to large inter-individual variations, audiometry screening remains important with respect to the detection of individual outliers. Objectives: Tobramycin is frequently prescribed for CF patients. In this study, hearing loss due to cumulative tobramycin exposure in adult CF patients was investigated. Patients and methods: We retrospectively investigated 19 patients with both baseline and follow-up audiometry before and after repeated courses of intravenous tobramycin (10 mg/kg/day in twice daily administrations for 3 weeks). Pure tone audiometry was performed at 0.250–16 kHz. Results: After repeated courses of tobramycin (median 3, range 1–8), the mean increase per frequency was 2.1 dB (median 0.5 dB, SD 12.6) with large (inter-individual) variations (range –23.5 to 34.5 dB). The pure tone averages (PTA) at 1-2-4 kHz and 8-10-12 kHz increased 1.4 dBHL and 2.3 dBHL, respectively, but were neither statistically significant, nor correlated with the cumulative tobramycin exposure.

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

No hearing loss after repeated courses of tobramycin in cystic fibrosis patients

The effects of intravenous tobramycin on renal tubular function in children with cystic fibrosis

Background Tobramycin, used to treat respiratory exacerbations in cystic fibrosis (CF), is also a renal tubular toxin. Tubular dysfunction leads to increased urinary levels of the proximal tubular lysosomal enzyme, N-acetyl-beta- d-glucosaminidase (NAG) and the proximal tubular protein, retinol-binding protein (RBP). Hypermagnesuria and resulting hypomagnesaemia are indicative of more severe tubular damage, occasionally seen following repeated courses of intravenous tobramycin. Using these biochemical markers we studied the effect of a 2-week course of this agent on tubular function. Methods Twenty-two children (11 boys) with CF were studied. Median age = 10.9 years, range 3.1–16.4 years. All had a normal predicted glomerular filtration rate (pGFR). They received tobramycin 3 mg/kg/dose tds. Urinary NAG, RBP, creatinine and plasma magnesium and creatinine were assayed: a) immediately before commencing tobramycin b) immediately following the course c) 4 weeks after the end of the course. Results Mean log UrNAG and UrRBP rose significantly between time points a) and b) before falling to almost pre-treatment levels by time c). Using two way ANOVA analysis the results for UrNAG and UrRBP were both highly statistically significant ( p < 0.0001). Paired t-tests on the logged values revealed highly significant differences between all time points for UrNAG and in the case of UrRBP for all other than a) compared to c). In all patients plasma magnesium and pGFR remained within normal limits. Conclusions Intravenous tobramycin produces acute tubular injury, which showed evidence of almost complete recovery after 4 weeks. The insult to the tubules was not sufficient to produce hypomagnesaemia in our study group. To assess cumulative tubular damage in more detail it would be necessary to repeat this study after further courses of tobramycin. We recommend monitoring plasma magnesium during courses of intravenous tobramycin.

A pilot case control follow-up study on hearing in children treated with tobramycin in the newborn period

Objective: To assess the occurrence of hearing loss in children due to neonatal exposure to long courses of tobramycin and/or high tobramycin serum concentrations. Methods: This was a pilot case–control study in 3–4-year old children. Data on tobramycin administration were abstracted from the patient files of an earlier study. Patients exposed in the neonatal period to either long courses (>7 days) or high serum concentrations of tobramycin constituted the study group. The control group consisted of patients without tobramycin exposure. Patients were matched for other risk factor according to criteria of the joint committee on infant hearing. All patients underwent the following investigations: otoscopy and pneumatic otoscopy, followed by impedance audiometry, to exclude middle ear effusion. Click-evoked oto-acoustic emissions (ce-OAE) as well as distortion product oto-acoustic emissions (dp-OAE), tested at f2 frequencies ranging from 1 to 10 kHz, were measured to assess hearing. All patients with abnormal ce-OAE results underwent brainstem electric response audiometry (BERA) as well. Since aminoglycoside ototoxicity is usually bilateral, results were compared per patient and not per ear. Results: A total of 29 patients were tested. Eleven patients were excluded due to middle ear effusion. Data for 18 patients were analyzed. In the tobramycin treated group ( n=9) both ce-OAE and dp-OAE (at all tested frequencies) were not detectable in six ears of three patients. All other patients had normal ce-OAE's as well as normal dp-OAE's in this frequency range. Difference between the tobramycin treated and control group for OAE as well as dp-OAE showed a trend ( P=0.08). In all three patients with undetectable emissions BERA confirmed a cochlear loss of 60–70 dB at 3 kHz in both ears. These three patients had the longest total exposure to tobramycin: 20–24 days and 84–92 mg/kg, respectively. No relation to either peak or trough serum concentrations could be detected. Conclusion: There was no statistical relation between hearing loss and tobramycin exposure, probably due to sample size. Our results do indicate a need for a case–control follow-up study of hearing in neonates exposed to long courses of aminoglycosides.

Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis

OBJECTIVETo compare once daily with thrice daily tobramycin for treatment of Pseudomonas aeruginosainfection in patients with cystic fibrosis.DESIGN22 patients with cystic fibrosis, mean (SD) age 11 (3.4) years (range 5.6–19.3),...

Tobramycin-induced hearing loss in a patient with end-stage renal disease

A 60-year-old female undergoing chronic hemodialysis for end-stage renal disease was evaluated audiologically for the frequencies 0.25, 0.5, 1, 2, 3, 4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 kHz over a 7-week period during and after a 4-week course of tobramycin used for control of diverticulitis. Blood levels of the medication were monitored serially and pre- and post-hemodialysis. BAR audiometrics were administered periodically over the 7-week period. Despite conservative medical management where blood levels of medication were allowed to peak at 7 mcg/ml concentration and trough at 2 mcg/ml, the patient demonstrated progressive hearing loss which commenced in the extended high tones and progressively affected lower tone acuity. By the completion of the 7-week period, 6 and 8 kHz were just beginning to show decrease in hearing function while lower primary speech frequencies remained unaffected. BAR data demonstrated no overt changes in wave latencies. Other BAR findings and blood studies were explored with respect to hearing loss findings.

Chemotherapy of chronic infections with mucoid Pseudomonas aeruginosa in lower airways of patients with cystic fibrosis.

The bacteriological effect of chemotherapy against Pseudomonas aeruginosa (Ps.ae.) in lungs of patients with cystic fibrosis is reviewed. During a 5-year period 49 children and adults were treated with 190 courses of different antibiotics. The mucoid strains of Ps.ae. disappeared in 72.0% of the courses in which a combination of tobramycin and carbenicillin was employed. Tobramycin given alone had only bacteriological effect in 26.6% of the courses. Colimycin alone or in combination with carbenicillin had no effect. In 18 patients who received subsequent courses of tobramycin and combination of tobramycin and carbenicillin a significant difference in favour of the combination therapy was found, also in cases with many precipitins against Ps.ae. in serum. In 74.5% of the initially successful courses the patients were recolonized with Ps.ae. within 1 month. No nephrotoxic or ototoxic side effects were demonstrated in spite of the high doses of tobramycin (10 mg/kg/24 h) emmployed and the repeated courses.

Tobramycin in the treatment of severe and complicated urinary tract infections.

Tobramycin is an aminoglycoside aminocyclitol antibiotic with pharmacological similarities to gentamycin. Twenty-one of 30 patients with a severe or complicated Gram-negative urinary tract infection were cured by treatment with a 5-day course of tobramycin. No side effects were noted. This drug should prove beneficial for the treatment of severe Gram-negative sepsis, and promises to be particularly valuable for infections due to Pseudomonas aeruginosa. Dosage schedules for administering tobramycin to patients with renal function impairment are presented, together with some observations on its intravenous injection by bolus. A single dose of tobramycin has proved effective for initiating the antibacterial treatment of patients with acute pyelonephritis. The important concept of the differing concentrations of an antibiotic in the urine from kidneys of unequal function is discussed.

Tobramycin in chronic recurrent urinary tract infections

A total of 32 adult patients of both sexes with chronic recurring urinary tract infections were treated with tobramycin in a daily dose of 1.2 mg/kg of body weight. They were randomly allocated to receive the drug at 8 or 12 hour intervals by intramuscular injection. The overall immediate disappearance of bacteriuria after therapy was 78.1 per cent; 15 days later, the cure rate dropped to 60 per cent. There was no difference between the two schedules tested. Tolerance to tobramycin was excellent. No reaction was recorded at the injection site; audiometry (performed in nine patients) and laboratory tests done prior to and after therapy did not reveal any hematologic, hepatic and/or renal toxicity, with one exception. In a patient with chronic renal failure (a patient with a solitary kidney infected with a pseudomonas sp.) there was a consistent elevation of blood urea in two separate courses of tobramycin, returning to normal within two weeks after stopping the therapy.