Intravenous Tobramycin Research Articles

Aminoglycoside use in cystic fibrosis: therapeutic strategies and toxicity

This review summarizes the recent literature regarding the uses for and toxicity of aminoglycosides in cystic fibrosis (CF). Aminoglycosides are indicated in the management of acute exacerbations of CF, to control chronic infection, and to eradicate Pseudomonas aeruginosa after recent acquisition. Intravenous gentamicin is associated with increased risk of acute kidney injury, whereas intravenous tobramycin is less so. Studies regarding chronic kidney disease related to cumulative aminoglycoside exposure are currently conflicting, but a prevalence of up to 42% has been reported. A single daily dose of intravenous tobramycin is as effective as a thrice-daily regimen and is less nephrotoxic. A large paediatric series has recently reported a prevalence of hearing impairment of 4.5%, and a small adult cohort has found a 30% rate of vestibulotoxicity. Neither appears to be related to cumulative exposure. In recent years, the well known toxicities of aminoglycosides have been investigated in CF populations. It appears that intravenous tobramycin is well tolerated in the kidneys compared with gentamicin, and that cumulative exposure may result in chronic kidney disease. Hearing loss and vestibulotoxicity are also prevalent. These important epidemiological studies lay the groundwork to design interventional studies to reduce toxicity.

Inhaled versus systemic antibiotics and airway inflammation in children with cystic fibrosis and Pseudomonas

Inhaled tobramycin has been shown to transiently clear Pseudomonas from lower airways in early cystic fibrosis (CF), but does not markedly reduce lung inflammation, a key factor in disease progression. Test the hypothesis that systemic antibiotics are more effective than inhaled antibiotics for reducing lower airways inflammation. Clinically stable CF children with recent Pseudomonas were randomized to receive 4 weeks of inhaled tobramycin or 2 weeks of systemic antibiotics (intravenous ceftazidime and tobramycin). Bronchoalveolar lavage fluid was obtained just before and 4-6 weeks after treatment. The primary outcome was change in % neutrophils in lavage fluid. Fifteen subjects (inhaled = 6, systemic = 9) completed the protocol. Three Systemic Group subjects could not have central venous access established and were treated with oral ciprofloxacin (plus inhaled tobramycin) for 2 weeks as an alternative "systemic" regimen, per protocol. Groups were well matched in age, markers of disease severity, and initial % neutrophils. The Systemic Group showed a modest median change in percent neutrophils (-7%) which was not statistically significant compared to inhaled (+5.4%, P = 0.07). However, the Systemic Group had significantly greater reductions in total cells (-50% vs. -3%, P < 0.01) and neutrophils (-74% vs. -10%, P = 0.02) per ml lavage fluid. Both groups had reduced bacterial quantity after treatment, but there was no significant difference between groups. In clinically stable children with CF, systemic antibiotics result in greater short-term reduction in lower airways inflammation than inhaled antibiotics.

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.

Resurgence of Pseudomonas Endocarditis in Detroit, 2006-2008

A resurgence of endocarditis due to Pseudomonas aeruginosa was seen in 10 injection drug users (IDUs) in Detroit between 2006 and 2008 (6 men, 4 women; mean age, 48.1 yr). All patients tested negative for the human immunodeficiency virus (HIV). Five patients had left-sided endocarditis of the mitral valve and/or the aortic valve; 3 of 5 patients had prosthetic valve endocarditis. Four of 10 patients had right-sided endocarditis of the tricuspid valve alone. One patient had bilateral involvement of the aortic and tricuspid valves. Nine patients had Pseudomonas endocarditis (PsE); 1 patient had mixed endocarditis with P. aeruginosa and Candida parapsilosis. Seven of 10 patients were treated with a combination of intravenous cefepime, 4-6 g/d, plus high-dose tobramycin (HDT) for at least 6 weeks. Tobramycin, 8 mg/kg per day, was given as a single daily dose intravenously, aiming for peak serum levels of 18-22 microg/mL and trough levels of <1 microg/mL. The patient with mixed endocarditis was also treated with fluconazole. Two patients initially treated with other antipseudomonal regimens, including cefepime alone and piperacillin/tazobactam plus tobramycin, failed treatment and were switched to cefepime and HDT. A third patient was switched to cefepime and ciprofloxacin because of nephrotoxicity. Two patients developed nephrotoxicity to tobramycin; 1 patient developed ototoxicity. The overall medical cure rate for both left-sided and right-sided disease was 80% (4/5). All 5 patients who required surgery survived (5/5; 100%). Overall outcome was 90% (9/10). Indications for valve replacement were recurrent Pseudomonas bacteremia (n = 3), recurrent bacteremia and congestive heart failure (n = 1), and persistent bacteremia and fungemia (n = 1). Tricuspid valvulectomy with valve replacement was successful in 2 patients and in a third patient who had successful replacement of both the tricuspid and the aortic valve for recurrent bacteremia and congestive heart failure. Two patients with pure left-sided prosthetic valve endocarditis underwent successful repeat valve replacements. Although this is a small series, the overall mortality rate (1/10; 10%) was low. The patient who did not survive had left-sided involvement of the aortic valve and could not undergo surgery because of a large embolic cerebral infarct. The mortality rate of left-sided disease in the current series was 16.7% (1/6 including the patient with tricuspid and aortic valve PsE) compared to 60% in a series of 15 patients reported in 1990.Our current antimicrobial regimen for PsE consists of a combination of cefepime, 6 g/d, in 3 divided doses, plus HDT, 8 mg/kg per day, given as a single daily dose for 6 weeks. For cefepime-resistant Pseudomonas, imipenem, 4-6 g/d, or meropenem, 6 g/d, plus HDT has been successful. For right-sided disease refractory to medical therapy, surgical intervention is recommended if Pseudomonas bacteremia persists for 2 weeks on appropriate antimicrobial therapy or if bacteremia recurs after a 6-week course of treatment. Tricuspid repair/reconstruction or valvulectomy with valve replacement plus combined antipseudomonal regimen may be the optimal therapy for refractory right-sided endocarditis. This approach not only may prevent the development of severe and permanent impairment of right ventricular function, which is a complication of valvulectomy alone without valve replacement, but also may cure the infection. For left-sided disease, surgery is recommended if blood cultures remain positive for 7 days on appropriate antimicrobial therapy or if Pseudomonas bacteremia recurs after completion of a 6-week course of the combined regimen.

Continuous versus Intermittent Infusions of Ceftazidime for Treating Exacerbation of Cystic Fibrosis

The present multicenter, randomized crossover study compared the safety and efficacy of continuous infusion with those of short infusions of ceftazidime in patients with cystic fibrosis. Patients with chronic Pseudomonas aeruginosa colonization received two successive courses of intravenous tobramycin and ceftazidime (200 mg/kg of body weight/day) for pulmonary exacerbation administered as thrice-daily short infusions or as a continuous infusion. The primary endpoint was the variation in the forced expiratory volume in 1 s (FEV1) during the course of antibiotic treatment. Sixty-nine of the 70 patients enrolled in the study received at least one course of antibiotic treatment. The improvement in FEV1 at the end of therapy was not statistically different between the two treatment procedures (+7.6% after continuous infusion and +5.5% after short infusions) but was better after continuous ceftazidime treatment in patients harboring resistant isolates (P < 0.05). The interval between the course of antibiotic treatments was longer after the continuous infusion than after the short infusion of ceftazidime (P = 0.04). The mean serum ceftazidime concentration during the continuous infusion was 56.2 +/- 23.2 microg/ml; the mean peak and trough concentrations during the short infusions were 216.3 +/- 71.5 and 12.1 +/- 8.7 microg/ml, respectively. The susceptibility profiles of the P. aeruginosa isolates remained unchanged and were similar for both regimens. Quality-of-life scores were similar whatever the treatment procedure, but 82% of the patients preferred the continuous-infusion regimen. Adverse events were not significantly different between the two regimens. In conclusion, the continuous infusion of ceftazidime did not increase its toxicity and appeared to be as efficient as short infusions in patients with cystic fibrosis as a whole, but it gave better results in patients harboring resistant isolates of P. aeruginosa.

Neuralgic Amyotrophy Associated with Antibiotic Therapy

To report a case of neuralgic amyotrophy associated with antibiotic therapy. A 22-year-old male with cystic fibrosis had been nonadherent to treatment for 4 years; when he returned to the clinic with symptoms, his forced expiratory volume in 1 second dropped from 84% predicted to 43% predicted. He was admitted to the hospital for treatment after failing to improve on oral ciprofloxacin and inhaled tobramycin. Treatment was initiated with intravenous tobramycin 560 mg daily and piperacillin/tazobactam 4.5 g infused every 6 hours. He continued inhaled tobramycin 300 mg twice daily, his home doses of pancreatic replacement enzymes and vitamins, albuterol 2.5 mg by high flow nebulizer (HFN) 4 times daily, and dornase alpha 2.5 by HFN daily. Sputum cultures were positive for methicillin-resistant Staphylococcus aureus, and intravenous vancomycin 1 g every 8 hours was added to the treatment regimen on hospital day 7. The patient developed bilateral shoulder pain followed by decreased function of his upper extremities 2 days later. He was treated with oral ibuprofen 600 mg every 6 h and oral cyclobenzaprine 5 mg daily, which improved his pain, but the shoulder stiffness remained throughout his hospital stay and persisted for 2 months following discharge. These symptoms resolved but recurred rapidly (within 24 h) and were more debilitating following a second exposure to the same antibiotics at the same doses 8 months later when the patient was readmitted for treatment of another cystic fibrosis-related pulmonary exacerbation. To our knowledge, this is the first case report illustrating neuralgic amyotrophy triggered by exposure to the antibiotics vancomycin, tobramycin, and piperacillin/tazobactam. After analysis of the case, ruling out other possibilities and using the Naranjo probability scale, we found that there is a highly probable likelihood that the symptoms presented by our patient were secondary to his drug therapy. Neuralgic amyotrophy is a rare condition of unknown etiology that has never before been associated with administration of these antibiotics, individually or in combination. Because of the specifics of the clinical history, we were unable to ascertain whether this complication was due to a single antibiotic or to the combination. It is quite possible that vancomycin was the only culprit, but impossible to ensure with the available evidence. Clinicians should be aware of this adverse reaction when facing similar complex neurologic symptoms in patients who are receiving the antibiotic treatment described here, especially vancomycin.

Successful treatment of cepacia syndrome with combination nebulised and intravenous antibiotic therapy

We report the case of successful treatment of a 31-year-old lady with cystic fibrosis and an en-bloc liver–pancreas transplant, who developed cepacia syndrome on a background of chronic infection with the ET12 epidemic strain of Burkholderia cenocepacia. Combination therapy with nebulised and intravenous meropenem and tobramycin led to clinical improvement with a return to baseline function and complete resolution of the acute chest X-ray changes.

Tobramycin-Induced Hepatotoxicity

To report a case of tobramycin-induced hepatotoxicity. A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3-6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values. This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive timeline present, lack of specific symptoms, and unnecessary risk to the patient. Although no other case reports on this interaction have been published through October 9, 2007, historical data from tertiary sources reveal the possibility of aminoglycoside-induced hepatotoxicity; therefore, tobramycin-induced hepatotoxicity cannot be ruled out in this patient. Clinicians should be aware of this adverse event.

Target concentration intervention is needed for tobramycin dosing in paediatric patients with cystic fibrosis – a population pharmacokinetic study

* Two recent papers have been published which have attempted to build a full population pharmacokinetic model for tobramycin in children with cystic fibrosis. * However, neither study was able to provide any information about between-subject variability (BSV) and between-occasion variability (BOV), which is necessary to justify and draw conclusions about the use of target concentration intervention (TCI). * In the publications no simulations were provided to show any new directions or evaluate current therapy. * This study provides sound evidence that TCI must be undertaken in this patient group, as the BOV is significantly less than the BSV. * The simulations from this model clearly show that current dosing and monitoring methods will not achieve the necessary targets to maximize the pharmacokinetic-pharmacodynamic relationships of aminoglycosides in this patient group. * The model presented is able to be easily incorporated into Bayesian dose individualization software, e.g. Abbottbase or TCIworks, to achieve dosing targets more accurately. The primary aim was to estimate the population pharmacokinetic parameters of once-daily intravenous (i.v.) tobramycin in paediatric cystic fibrosis (CF) patients and to investigate the influence of covariates. The second aim was to assess the need for target concentration intervention (TCI) for tobramycin in this patient group. Retrospective demographic, dosing and concentration data were collected from 35 CF patients (21 female, 14 male) aged 0.5-17.8 years, from whom 318 tobramycin plasma concentrations were available. NONMEM was used to estimate the population pharmacokinetics of tobramycin. Simulations were performed using weight-based dosing with a weight from a covariate distribution model to evaluated current dosing schedules and monitoring practices. A two-compartment model best described the data with population parameter estimates for clearance of central compartment (CL) of 6.37 l h(-1) per 70 kg; volume of central compartment (V(c)) of 18.7 l per 70 kg; intercompartmental clearance (Q) of 0.393 l h(-1); and volume of peripheral compartment (V(per)) of 1.32 l. The inclusion of total body weight as covariate reduced the random component of between-subject variability in CL from 50.1% to 11.7% and in V(c) from 62.2% to 11.6%. The between-occasion variability on CL was estimated in the final model as 6.5%. Simulations show that one dose does not fit all and TCI and dose adjustment are required. This study provides the first pharmacokinetic model of once-daily i.v. tobramycin for the use of target concentration intervention in paediatric CF patients.

Efficacy and safety of intravenous meropenem and tobramycin versus ceftazidime and tobramycin in cystic fibrosis

Background Cystic fibrosis (CF) is characterized by chronic bacterial broncho-pulmonary infection. Although intravenous (IV) antibiotic therapy is regarded as standard treatment in CF, only few randomised trials comparing different antibiotic compounds exist. Methods We report on a prospective multicenter interventional trial of IV meropenem (120 mg/kg/day) or IV ceftazidime (200–400 mg/kg/day), each administered together with IV tobramycin (9–12 mg/kg/day). Outcome measures were changes in lung function, microbiological sputum burden and blood inflammatory marker. Liver and renal function values were measured to assess safety. Results One hundred eighteen patients (59/59) were included into the study with the following indications: first infection of P. aeruginosa ( n = 6), acute pulmonary exacerbation ( n = 34) and suppression therapy of chronic P. aeruginosa colonization ( n = 78). Both treatments improved lung function measures, bacterial sputum burden and CRP levels with no differences between treatment groups observed. A significant higher elevation for alkaline phosphatase ( p < 0.0001) was observed for patients in the meropenem/tobramycin group. Conclusions IV antibiotic therapy in CF patients with meropenem/tobramycin is as effective as with ceftazidime/tobramycin regarding lung function, microbiological sputum burden and systemic inflammatory status. Hepato-biliary function should be monitored carefully during IV treatment, possibly important in CF patients with pre-existing liver disease.

Aerosolized Tobramycin in The Treatment of Ventilator-Associated Pneumonia: A Pilot Study

To evaluate the efficacy and safety of inhaled tobramycin (TOBI) in the treatment of ventilator-associated pneumonia (VAP) in a randomized, double-blind pilot study. Ten patients from a cohort of 108 mechanically ventilated patients with documented clinical and bacteriological evidence of VAP caused by Pseudomonas aeruginosa or Acinetobacter spp. in the surgical and trauma intensive care units of a university teaching hospital were randomized to receive either TOBI (n = 5) or intravenous tobramycin (TOBRA; n = 5). The two groups were similar in their Acute Physiology and Chronic Health Evaluation (APACHE) score, Clinical Pulmonary Infection Score (CPIS), and Multiple Organ Dysfunction Score (MODS) prior to randomization. The primary outcome measure was resolution of pneumonia. The CPIS and MODS were used as objective indicators of clinical progress. All TOBI patients had clinical resolution of VAP. Two TOBRA patients were considered failures. One had deterioration in MODS, and the other had doubling of his serum creatinine concentration. The patients treated with TOBI may have had more ventilator-free days than those receiving TOBRA, but the difference was not statistically significant owing to the small sample size (24 +/- 3 vs. 14 +/- 13 days; p = 0.12). Aerosolized tobramycin for the treatment of VAP appeared safe and effective in this pilot study. A larger study is warranted to determine if aerosolized tobramycin will lead to better outcomes than intravenous tobramycin when used for the treatment of VAP.

Pharmacokinetic profile of once daily intravenous tobramycin in children with cystic fibrosis

Once-daily tobramycin in patients with cystic fibrosis (CF) is a more convenient dosing regimen than thrice daily dosing. There are limited data on the pharmacokinetic (PK) profile for once-daily tobramycin in patients with CF. The aim of this study was to define the PK parameters for once-daily tobramycin in children with CF and develop an algorithm for therapeutic drug monitoring dosing. CF patients admitted to hospital were commenced on once-daily intravenous tobramycin (12 mg/kg/day) and ticarcillin/clavulinic acid. Serum tobramycin levels were taken at 30 min, 2-4 h and 12 h post dose. Data points for the PK model included: age, sex, weight, tobramycin dose, time of tobramycin doses and levels, tobramycin levels. WinNonMix was used to obtain the PK parameters. Forty-four children with 86 admissions who were aged 9 months-20 years were included. A one-compartment intravenous infusion model with first order elimination kinetics produced the best model. Population parameters were: volume of distribution (V(d)) = 0.267 L/kg (95% confidence interval (CL) 0.260-0.272), clearance (CL) 0.103 L/kg/h (95% CI 0.098-0.107) and half-life (t(1/2)) 1.82 (95% CI 1.77-1.88) h. Once the population model was established post hoc analysis was used to calculate individual subject predictions. Plots of individual prediction curves agreed well with observed values. This study has established an algorithm for routine monitoring of once-daily tobramycin in children with CF. Satisfactory serum levels of tobramycin were obtained with a dose of 12 mg/kg/day and a regimen algorithm that uses only one measurement to monitor the plasma concentration is suggested.

Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?

Once-daily administration of aminoglycosides in cystic fibrosis (CF) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day. However, the choice of the most suitable PK/PD index (C(max)/MIC versus AUC(24)/MIC) to ensure optimum clinical outcome in this patient population is not clear. In a single-centre, open, randomized, controlled, non-blinded study 33 adult CF patients (20 females, 19-37 years) were treated with intravenous tobramycin (10 mg/kg/day) for 14 days given either as single dose once a day (Q24; 17 patients) or divided into three equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage predicted forced expiratory volume in 1 s (FEV(1)% pred.). FEV(1)% pred. improved significantly for both treatments. There was a log-linear relationship between C(max)/MIC and FEV(1)% pred. and AUC/MIC and FEV(1)% pred. for both treatments. For equal values of AUC24/MIC, however, Q24 treatment provided better improvement in lung function than Q8 dosing, whereas C(max)/MIC did not show any dosing interval dependence. A statistically significant increase was observed for MIC (day 1) versus MIC (day 14) for Q24 treatment, however, no such difference was observed for Q8 treatment. The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC. Outcome prediction of AUC(24)/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.

In-vivo impact of the MexXY efflux system on aminoglycoside efficacy in an experimental model of Pseudomonas aeruginosa pneumonia treated with tobramycin

Aminoglycosides are of major importance in treating Pseudomonas aeruginosa pneumonia (PAP). However, their efficacy may be compromised by low-level resistance caused by the inducible MexXY multidrug efflux pump. In the present study, the impact of the MexXY efflux pump was investigated in vivo in an experimental model of PAP in rabbits treated with intravenous tobramycin. Three strains were used to induce PAP in rabbits: PAO1 (wild-type strain; MIC 1 mg/L), mutant 11B (mexX::Tn501; no expression of MexXY; MIC 0.5 mg/L) and mutant MutGR1 (MexZ null; constitutive expression of MexXY; MIC 2 mg/L). Five hours after inoculation, treatment with tobramycin (10 mg/kg) was implemented (peak serum concentration 30 mg/L). The animals were killed humanely 48 h after inoculation, and the residual pulmonary bacterial concentration was determined. Selection of bacteria expressing MexXY was determined by plating lung homogenates on agar plates containing antibiotic. Mean bacterial counts (log(10) CFU/g) for treated vs. untreated rabbits were 6.26 and 8.13 (p < 0.0001), 6.00 and 8.38 (p < 0.001), and 7.25 and 8.79 (p 0.04) for PAO1, 11B and MutGR1, respectively, with an overall mortality rate of 0% vs. 8.9% (p < 0.01). MexXY-overexpressing bacteria were recovered from three (21%) treated rabbits. The C(max)/MIC ratio was the parameter that was best associated with tobramycin efficacy. The bacteria overexpressing MexXY, recovered from lung, occurred with a C(max)/MIC window of 19-26. It was concluded that the experimental PAP model highlights poor tobramycin bacteriological efficacy in vivo, contrasting with survival gain, and that the contribution of the MexXY system to this low level of tobramycin efficacy is modest. Finally, this model appears to be suitable for the investigation of new anti-pseudomonal therapeutic strategies.

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.

Orbital cellulitis in a burned child

A 6-month-old was admitted to our burn center for a 15% TBSA scald burn to his lower extremities, groin, buttocks and abdomen. His past medical history was significant for hydrocephalus. The patient became febrile on hospital day 6. Blood cultures showed infection with methicillin resistant Staphylococcus aureus (MRSA). The patient completed a course of intravenous vancomycin and tobramycin. On hospital day 42 the patient became febrile and developed swelling of the right lower leg. Lower extremity Doppler ultrasound revealed a thrombosis of his common iliac vein. Blood cultures revealed MRSA. Three days later he was noted to have right upper eyelid edema (Plate 1). At this time the ophthalmology service was consulted. On examination, the child was intubated and mildly sedated. Visual acuity was difficult to assess secondary to his level of sedation. The pupils were brisk with no evidence of an afferent papillary defect. The child was moving his eyes and grossly there appeared to be no ocular motility deficit. The right upper lid was swollen with loss of the normal lid crease. The eyelid was mildly erythematous with no palpable fluctuance. Manual palpation of the right orbit revealed increased resistance as compared to the left orbit. The portable slit lamp exam

Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial

Intravenous tobramycin (three-times daily) is widely used for pulmonary exacerbations in patients with cystic fibrosis who have chronic Pseudomonas aeruginosa infection. We undertook a double-blind, randomised controlled trial to assess the safety and efficacy of once versus three-times daily tobramycin in these patients. 244 patients from 21 cystic-fibrosis centres in the UK were randomly assigned to once or three-times daily tobramycin (with ceftazidime) for 14 days. Treatment was given as 30-min infusions of tobramycin in 0.9% saline. Primary outcome measure was change in forced expiratory volume in 1s (FEV1), over the 14 days of treatment, expressed as a percentage of the predicted normal value for age, sex, and height. We also measured the change in FEV1 expressed as a percentage of baseline. Secondary outcomes included change in serum creatinine. The study was powered for equivalence, and primary analysis was per protocol. 219 patients (107 once daily, 112 three-times daily) completed the study per protocol. None was lost to follow-up, although 20 discontinued intervention. Of 122 patients assigned to once daily treatment, three did not receive the study regimen. The mean change in FEV1 (% predicted) over 14 days was similar on the two regimens (10.4% [once daily] vs 10.0% [three-times daily]; adjusted mean difference 0.4% [95% CI -3.3 to 4.1]). Mean% change in FEV1 from baseline was also similar in both treatments (21.9% vs 22.1%; -0.1% [-8.0 to 7.9]). There was no significant difference in% change in creatinine from baseline (-1.5% [once daily] vs 1.7% [three-times daily]). However, in children, once daily treatment was significantly less nephrotoxic than was thrice daily (mean% change in creatine -4.5% [once daily] vs 3.7% [thrice daily]; adjusted mean difference -8.0%, 95% CI -15.7 to -0.4). No patients developed hearing loss during the study, although two reported acute dizziness and were withdrawn from the study. Intravenous tobramycin has equal efficacy if given once or three-times daily (with ceftazidime) for pulmonary exacerbations of cystic fibrosis. The once daily regimen might be less nephrotoxic in children.

Determination of tobramycin in saliva is not suitable for therapeutic drug monitoring of patients with cystic fibrosis

Background Tobramycin, used in the treatment of infections caused by Gram-negative bacteria, requires therapeutic drug monitoring (TDM) due to its narrow therapeutic index. The collection of blood for these assays may cause pain and trauma to the child and/or be difficult because of limited access to appropriate blood vessels. We undertook an evaluation of the role of saliva concentrations in the TDM of once-daily tobramycin therapy in patients with cystic fibrosis. Methods Fourteen patients (mean age 15 years) with cystic fibrosis were enrolled at Women's and Children's Hospital, Adelaide (WCH). All patients received once-daily dose of intravenous tobramycin for 2–3 weeks and had plasma levels measured once a week. At the same time of blood sampling at 1 and 6 h after initiation of tobramycin infusion, the patients also provided saliva samples. For collection of saliva, the Salivette® (Sarstedt Laboratories) system was used which was developed specifically for saliva sampling. Concentrations in blood and saliva were measured by the Beckman Synchron CX® system, which is utilized for routine assays of plasma tobramycin. Results and conclusion Tobramycin could not be detected in saliva within the first 6 h after a once-daily dosing. Therefore, plasma cannot be substituted with saliva for the TDM of tobramycin using the clinical routines at WCH.

A reevaluation of empiric therapy for peritoneal dialysis-related peritonitis

A reevaluation of empiric therapy for peritoneal dialysis-related peritonitis

Staphylococcus capitis Endocarditis

Staphylococcus capitis Endocarditis