Tobramycin Systemic Absorption in Lung Transplant Recipients Treated With Inhaled Tobramycin: A Cohort Study.

Inhaled tobramycin treatment has been associated with nephrotoxicity in some case reports, but limited data are available about serum levels and its possible systemic absorption in lung transplant recipients (LTR). We conducted a single-center, observational and retrospective study of all adult (>18 years old) LTR treated with inhaled tobramycin for at least 3 days between June 2019 and February 2022. Trough serum levels were collected and >2 µg/mL was considered a high drug level. The primary outcome assessed the presence of detectable trough levels, while the secondary outcome focused on the occurrence of acute kidney injury (AKI) in individuals with detectable trough levels. Thirty-four patients, with a median age of 60 years, were enrolled. The primary indications for treatment were donor bronchial aspirate bacterial isolation (18 patients) and tracheobronchitis (15 patients). In total, 28 patients (82%) exhibited detectable serum levels, with 9 (26%) presenting high levels (>2 µg/mL). Furthermore, 9 patients (26%) developed acute kidney injury during the treatment course. Median trough tobramycin levels were significantly elevated in invasively mechanically ventilated patients compared to non-ventilated individuals (2.5 µg/mL vs. 0.48 µg/mL) (p < 0.001). Inhaled tobramycin administration in LTRs, particularly in those requiring invasive mechanical ventilation, may result in substantial systemic absorption.

Contact allergy to topical ophthalmic medications: A retrospective single-centre study of three decades.

BACKGROUND: The prevalence of contact allergy to various ophthalmic medications appears to be rare; however, data on culprits, clinical relevance of sensitizations, and changes in frequency within recent decades are limited. OBJECTIVE: This study aimed to investigate the clinical relevance, risk factors, and prevalence of contact allergy to topical ophthalmic medications in patients suspected of allergic contact dermatitis to ophthalmic medication. METHODS: We retrospectively analysed patch test results and clinical data for 754 patients patch-tested with an ophthalmic medication series at our tertiary referral centre between January 1992 and December 2022. RESULTS: In total, 37.5% (283/754) of patch-tested patients had a contact allergy to at least one ophthalmic allergen, with 87.3% (247) being clinically relevant sensitization. Phenylephrine (31.8%, 192/604), povidone-iodine (29%, 27/93), and tobramycin (23%, 46/200) were the most important sensitizers. The incidence of contact allergies increased significantly in a linear manner (p = 0.008) from 20% to 44.1% within the study period. Male sex and age above 40 were risk factors for contact allergy to ophthalmic medication. CONCLUSIONS: One third of patch tested patients had allergic contact dermatitis to ophthalmic medication, particularly phenylephrine. Male sex and age above 40 years were independent risk factors and drove the linear increase in contact allergy to ophthalmic medications within the past 31 years.

Safety Profile of Seven-Day Intra-articular Antibiotic Irrigation for the Treatment of Chronic Periprosthetic Joint Infection: A Prospective Randomized Phase II Comparative Study.

BACKGROUND: Systemic intravenous antimicrobials yield poor outcomes during treatment of periprosthetic joint infection due to the inability to obtain minimum biofilm eradication concentrations. This study evaluated the safety of a novel method of optimized local delivery of intra-articular antibiotics (IAAs). METHODS: This was a Phase II, multicenter, prospective randomized trial evaluating safety of a rapid (seven-day) two-stage exchange arthroplasty with IAA irrigation compared to standard two-stage exchange. The Experimental Group received irrigation using 80 mg tobramycin daily with a 2-hour soak, followed by hourly irrigation using 125 mg vancomycin with a 30-minute soak via an intramedullary irrigation device. The Control Group received an antibiotic-loaded cement spacer with vancomycin (average 8.4 g) and tobramycin (average 7.1 g, total 16 g antibiotics). Both groups received 12 weeks of systemic antibiotics following Stage 2. Safety measures included adverse events, peak vancomycin/tobramycin serum concentrations (Experimental Group), blood transfusion, and mortality. There were thirty-seven patients randomized to the Experimental Group and 39 to control. There was no difference in baseline demographics or comorbidities. RESULTS: There were no antibiotic medication-related adverse events and 2 serious adverse events related to antibiotic instillation. Of 188 vancomycin peak measurements, 69% had detectable serum level concentrations, with all concentrations well below the maximum acceptable trough threshold of 20 µg/mL. Of the 103 tobramycin peak measurements, 45% had detectable levels, with all below the maximum acceptable peak threshold of 18 to 24 µg/mL. There was no difference in blood transfused per subject (Experimental: 655 mL versus Control: 792 mL; P = .4188). There were two (2) deaths in the Experimental Group and four (4) in the control. CONCLUSIONS: The use of IAA is safe with minimal systemic antibiotic exposure. There was no difference in the rates or severity of serious adverse events between groups. Further research is being conducted to examine treatment efficacy.

Tobramycin and antiglaucoma agents as increasing culprits of periorbital allergic contact dermatitis from topical ophthalmic medications: A 24-year study from Turkey.

BACKGROUND: Allergic contact dermatitis (ACD) from topical ophthalmic medications (TOMs) poses an additional disease burden to patients who already suffer from eye problems. OBJECTIVES: To investigate the epidemiological/clinical profile of patients with periorbital ACD from TOMs in Turkey. PATIENTS AND METHODS: This was a retrospective, cross-sectional, single tertiary centre study based on files of 75 patch tested patients with suspected periorbital ACD from TOMs among a total of 2801 consecutively patch tested patients with suspected ACD of any origin between 1996 and 2019. RESULTS: Periorbital ACD was diagnosed in 25 of 75 (33.3%) patients (female:male = 1.8:1; age range: 6-85 years) with suspected ACD from TOMs showing an overall prevalence of 0.9% (25/2801) among the whole patch test population. Atopy was not present. Tobramycin-containing TOMs were the most frequent culprits, followed by antiglaucoma preparations. Their frequency increased, whereas no new cases of neomycin-induced ACD were observed after 2011. Positivities with thimerosal were of unknown clinical relevance, while benzalkonium chloride (BAC) caused ACD in two patients. The diagnosis would be missed in each 20% of patients without performing day (D) 4 and D7 readings and strip-patch testing. Ten culprits were identified only by testing with patients' own TOMs in eight (32%) patients. CONCLUSIONS: Aminoglycosides, particularly tobramycin, were the leading cause of ACD from TOMs. The frequency of ACD from tobramycin and antiglaucoma medications increased after 2011. BAC was a rare but important allergen. Additional D4 and D7 readings, strip-patch testing, and testing with patients' own TOMs seem essential when patch testing with eye medications.

Acute kidney injury in cystic fibrosis patients treated with intravenous colistimethate sodium or tobramycin.

OBJECTIVES: Colistimethate sodium and tobramycin are important systemic antibiotics for treatment of cystic fibrosis (CF) pulmonary exacerbations but can induce acute kidney injury (AKI). We characterize the rate of AKI in CF patients treated with systemic colistimethate sodium compared with tobramycin. METHODS: This single-centre, retrospective cohort study included hospitalized CF patients treated with IV colistimethate sodium or tobramycin. The primary outcome was AKI defined using the RIFLE criteria. Multivariate logistic regression using a mixed model was performed to identify variables that were independently associated with AKI. RESULTS: Overall, 156 patients representing 507 care encounters were included. The OR of AKI was not increased with IV colistimethate sodium relative to IV tobramycin after adjusting for other potential predictor variables (aOR 1.00; 95% CI 0.16-6.03). The frequency of AKI was 9.5% across all encounters, 6.9% with IV colistimethate sodium and 9.9% with IV tobramycin, with RIFLE category R (risk) being the most common stage, accounting for 4.2% of encounters with IV colistimethate sodium and 9.2% with IV tobramycin. The concomitant use of another nephrotoxin (aOR 2.51; 95% CI 1.27-4.95) or the combination of vancomycin and piperacillin/tazobactam (aOR 5.95; 95% CI 2.05-17.3) were both associated with increased odds of AKI. CONCLUSIONS: Systemic treatment with colistimethate sodium or tobramycin in the CF patient population is associated with a similar rate of nephrotoxicity. However, clinicians should be mindful of the increased risk for AKI in patients treated with either IV colistimethate sodium or IV tobramycin when used concurrently with other nephrotoxic agents, particularly the combination of vancomycin and piperacillin/tazobactam.

Effects of long-term tobramycin inhalation solution (TIS) once daily on exacerbation rate in patients with non-cystic fibrosis bronchiectasis.

BACKGROUND: Use of long-term tobramycin inhalation solution (TIS) has been shown beneficial in cystic fibrosis (CF) and earlier findings also suggest a benefit in non-CF bronchiectasis. We investigated the efficacy and safety of maintenance TIS once daily (OD) in frequent exacerbating bronchiectasis patients chronically infected by different pathogens sensitive for tobramycin. OBJECTIVE: The primary outcome was the frequency of exacerbations during the 12-month study period. Secondary outcomes were time to first exacerbation, change in lung function and quality of life (QoL), bacterial analysis and safety. MATERIALS/PATIENTS: IN THIS MULTICENTER RCT PATIENTS AGED ≥ 18-YEAR-OLD WERE INCLUDED WITH CONFIRMED BRONCHIECTASIS AND ≥ 2 EXACERBATIONS IN THE PRECEDING YEAR. PATIENTS WERE ASSIGNED (1:1) TO RECEIVE TIS OR PLACEBO OD FOR 1-YEAR.: RESULTS: 58 patients were included of which 52 were analyzed in the mITT analysis. TIS reduced exacerbation frequency with a RR of 0.74 (95% CI 0.49-1.14) (p = 0.15). Within the TIS population a decrease in number of exacerbations was found (2; p = 0.00), which was also seen in the placebo-treated patients (1.5; p = 0.00). In the TIS-treated patients the QoL improved (LRTI-VAS p = 0.02 Leicester Cough p = 0.02) without additional safety concerns. No differences were found for the other secondary outcomes. CONCLUSION: Long-term TIS OD is a safe treatment modality and showed a non-significant reduced exacerbation frequency of 0.74 as compared to placebo in bronchiectasis patients chronically infected by tobramycin sensitive pathogens. TIS OD may be a potential therapeutic strategy in selected patients with bronchiectasis suffering from a high burden of disease. TRAIL REGISTRATION NUMBER: The BATTLE study was registered at Clinical trials.gov number: NCT02657473 . Date: 13 august 2016.

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

INTRODUCTION: 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. MATERIALS AND METHODS: 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. RESULTS: 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%. CONCLUSIONS: Advanced PK model-informed analysis predicted ototoxicity risk in patients with CF treated with tobramycin and demonstrated high test prediction.

Mode of bacterial killing affects the inflammatory response and associated organ dysfunctions in a porcine E. coli intensive care sepsis model.

BACKGROUND: Sepsis is often treated with penicillin-binding protein 3 (PBP-3) acting ß-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response. METHOD: Killed or live Escherichia coli were administrated as a 3-h infusion to 16 healthy pigs in a prospective, randomized controlled interventional experimental study. Cefuroxime was chosen as the PBP-3-active antibiotic and tobramycin represented the aminoglycosides. The animals were randomized to receive (I) bacteria killed by cefuroxime, (II) live bacteria, (III) bacteria killed by heat, or (IV) bacteria killed by the combination of cefuroxime and tobramycin. Plasma endotoxin, tumor necrosis factor alpha, interleukin-6, interleukin-10, leukocytes, and organ function were recorded at the start of the experiment and then hourly for 6 h. RESULTS: Differences in dynamics of concentration over time between the four treatment groups were found for the three cytokines (p < 0.001). Animals receiving cefuroxime-killed bacteria demonstrated higher responses than those receiving live (p < 0.05) or heat-killed bacteria (p < 0.01). The addition of tobramycin reduced the cefuroxime-induced responses (p < 0.001). The cytokine responses were associated with leucocyte activation that was further associated with pulmonary dysfunction and increases in lactate (p < 0.01). CONCLUSIONS: In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3-active antibiotic reduced that response.

Pharmacokinetics and safety of tobramycin nebulization with the I-neb and PARI-LC Plus in children with cystic fibrosis: A randomized, crossover study.

AIMS: We aimed to compare the pharmacokinetics (PK) and safety profile of tobramycin inhalation solution (TIS) using the I-neb device to the standard PARI-LC Plus nebulizer in children with cystic fibrosis. METHODS: A randomized, open-label, crossover study was performed. In 2 separate study visits, blood samples from 22 children were collected following TIS nebulization with I-neb (75 mg) and PARI-LC Plus (300 mg). Study visits were separated by 1 month, in which 1 of the study nebulizers was used twice daily. Tobramycin PK for both nebulizers was established using measured tobramycin concentrations and Bayesian PK modelling software. Hearing and renal function tests were performed to test for aminoglycoside associated toxicity. In addition to standard estimated glomerular filtration rate values, biomarkers for tubular injury (KIM-1 and NAG) were measured. Patient and nebulizer satisfaction were assessed. RESULTS: Inhalations were well tolerated and serum trough concentrations below the predefined toxic limit were reached with no significant differences in PK parameters between nebulizers. Results of audiometry and estimated glomerular filtration rate revealed no abnormalities. However, increased urinary NAG/creatinine ratios at visit 2 for both nebulizers suggest TIS-induced subclinical tubular kidney injury. Nebulization time was 50% shorter and patient satisfaction was significantly higher with the I-neb. CONCLUSIONS: Nebulization of 75 mg TIS with the I-neb in children with cystic fibrosis resulted in comparable systemic exposure to 300 mg TIS with the PARI-LC Plus and was well tolerated and preferred over the PARI-LC Plus. Long-term safety of TIS nebulization should be monitored clinically, especially regarding the effects on tubular kidney injury.

Vestibulotoxicity in a patient without renal failure after inhaled tobramycin.

Aminoglycoside antibiotics have a long history of use in the control of gram-negative bacterial infections, but their systemic use has been complicated by known ototoxicity and nephrotoxicity. Because of the utility of these medications in patients with frequent pulmonary infections, there has been a move towards the use of inhaled agents, in particular tobramycin, due to a lower rate of systemic complications. Inhaled tobramycin is generally consider to be safe from otologic complications, with only two previous reports of ototoxicity, both in patients who had underlying chronic renal disease. Here we present the first case of a patient developing isolated vestibular toxicity, without associated hearing loss or evidence of renal insufficiency, in a patient receiving inhaled tobramycin. This is an extremely rare complication of an inhaled aminoglycoside and underscores the importance of careful monitoring despite perceived safety.

Oral Tobramycin Prophylaxis Prior to Colorectal Surgery Is Not Associated with Systemic Uptake.

Preoperative oral prophylaxis with nonabsorbable antibiotics has been reported to reduce the risk of surgical site infections after colorectal surgery. This prospective study was conducted to evaluate the risk of toxic side effects by measuring postoperative serum tobramycin levels in patients who received a 3-day prophylaxis with tobramycin and colistin prior to colorectal surgery. In all patients, serum tobramycin concentrations were below the detection limit (0.3 mg/liter), implying a low risk of toxicity.

Systemic Absorption of Antibiotics From Antibiotic-Loaded Cement Spacers for the Treatment of Periprosthetic Joint Infection.

BACKGROUND: Two-stage treatment of periprosthetic joint infections involves placement of high-dose antibiotic-loaded cement spacers (ACSs). Reports of ACS-induced nephrotoxicity have raised concern regarding systemic absorption of antibiotics after ACS placement. We sought to characterize the serum concentrations of antibiotics that occur after ACS placement. METHODS: We performed a prospective study of patients with an infected primary total hip (THA) or knee arthroplasty (TKA) treated with standardized ACSs with vancomycin, gentamicin, and tobramycin. Serum antibiotic levels were collected weekly for 8 weeks. RESULTS: Twenty-one patients (10 THA, 11 TKA) were included. Mean serum gentamicin levels ranged between 0.275±0.046 and 0.364±0.163 mg/L; mean serum tobramycin levels ranged from 0.313±0.207 to 0.527±0.424 mg/L; and mean serum vancomycin levels ranged from 5.46±6.6 to 15.34±9.6 mg/L. Serum antibiotic levels were detectable throughout the 8-week duration of ACS treatment. Regression analysis found that diabetes (coefficient 6.73, 95% CI 0.92-12.54, P < .05), blood urea nitrogen (coefficient 0.83, 95% CI 0.45-1.22, P < .001), number of cement doses (coefficient 3.71, 95% CI 0.76-6.66, P < .05), and use of systemic vancomycin (coefficient 6.24, 95% CI 2.72-9.75, P < .001) correlated with serum vancomycin levels. Patient age (coefficient -0.01, 95% CI -0.02 to 0, P < .01) and male sex (coefficient 0.20, 95% CI 0-0.41, P < .05) correlated with serum aminoglycoside level. CONCLUSION: Systemic absorption of antibiotics from high-dose ACS persists for at least 8 weeks. Patients should be monitored closely for complications related to systemic absorption of antibiotics from ACS treatment.

Nephrotoxicity After the Treatment of Periprosthetic Joint Infection With Antibiotic-Loaded Cement Spacers.

BACKGROUND: Treatment of periprosthetic joint infections commonly involves insertion of an antibiotic-loaded cement spacer (ACS). The risk for acute kidney injury (AKI) related to use of antibiotic spacers has not been well defined. We aimed to identify the incidence of and risk factors for AKI after placement of an ACS. METHODS: We performed a prospective cohort study of patients with an infected primary total hip or knee arthroplasty treated with ACSs with vancomycin, gentamicin, and tobramycin. Serum creatinine and glomerular filtration rate data were collected at baseline and weekly intervals for 8 weeks. Patients were classified into Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) stages to determine incidence of AKI. Risk factors for kidney injury were identified via regression analysis. RESULTS: A total of 37 patients (20 total knee arthroplasty and 17 total hip arthroplasty) were included. During the 8 weeks after ACS placement, 10 patients (27%) fit RIFLE criteria for kidney injury and 2 patients (5%) fit RIFLE criteria for kidney failure. No baseline patient characteristics were associated with development of AKI. CONCLUSION: Patients should be monitored closely for development of AKI after placement of ACSs for the treatment of periprosthetic joint infection. Further research into minimizing risk for AKI is warranted.

Topical treatments for blepharokeratoconjunctivitis in children.

BACKGROUND: Blepharokeratoconjunctivitis (BKC) is a type of inflammation of the surface of the eye and eyelids that involves changes of the eyelids, dysfunction of the meibomian glands, and inflammation of the conjunctiva and cornea. Chronic inflammation of the cornea can lead to scarring, vascularisation and opacity. BKC in children can cause significant symptoms including irritation, watering, photophobia and loss of vision from corneal opacity, refractive error or amblyopia.Treatment of BKC is directed towards modification of meibomian gland disease and the bacterial flora of lid margin and conjunctiva, and control of ocular surface inflammation. Although both topical and systemic treatments are used to treat people with BKC, this Cochrane review focuses on topical treatments. OBJECTIVES: To assess and compare data on the efficacy and safety of topical treatments (including antibiotics, steroids, immunosuppressants and lubricants), alone or in combination, for BKC in children from birth to 16 years. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE ( January 1946 to 11 July 2016), Embase (January 1980 to 11 July 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 July 2016. We searched the reference lists of identified reports and the Science Citation Index to identify any additional reports of studies that met the inclusion criteria. SELECTION CRITERIA: We searched for randomised controlled trials that involved topical treatments in children up to 16 years of age with a clinical diagnosis of BKC. We planned to include studies that evaluated a single topical medication versus placebo, a combination of treatments versus placebo, and those that compared two or multiple active treatments. We planned to include studies in which participants received additional treatments, such as oral antibiotics, oral anti-inflammatories, warm lid compresses and lid margin cleaning. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the results of the literature search (titles and abstracts) to identify studies that met the inclusion criteria of the review and applied standards as expected for Cochrane reviews. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included one study from the USA that met the inclusion criteria. In the study, 137 children aged zero to six years old with blepharoconjunctivitis were randomised to treatment in one of four trial arms (loteprednol etabonate/tobramycin combination, loteprednol etabonate alone, tobramycin alone or placebo) for 15 days, with assessments on days 1, 3, 7 and 15. We judged the study to be at high risk of attrition bias and bias due to selective outcome reporting. The study did not report the number of children with improvement in symptoms nor with total or partial success as measured by changes in clinical symptoms.All children showed a reduction in blepharoconjunctivitis grade score, but there was no evidence of important differences between groups. Visual acuity was not fully reported but the authors stated that there was no change in visual acuity in any of the treatment groups. The study reported ocular and non ocular adverse events but was underpowered to detect differences between the groups. Ocular adverse events were as follows: loteprednol/tobramycin 1/34 (eye pain); loteprednol 4/35 (eye pain, conjunctivitis, eye discharge, eye inflammation); tobramycin 0/34; placebo (vehicle) 0/34. The evidence was limited for all these outcomes and we judged it to be very low certainty.There was no information on clinical signs (aside from grade score), disease progression or quality of life. AUTHORS' CONCLUSIONS: There is no high-quality evidence of the safety and efficacy of topical treatments for BKC, which resulted in uncertainty about the indications and effectiveness of topical treatment. Clinical trials are required to test efficacy and safety of current and any future treatments. Outcome measures need to be developed which can capture both objective clinical and patient-reported aspects of the condition and treatments.

Detectable Concentrations of Inhaled Tobramycin in Critically Ill Children Without Cystic Fibrosis: Should Routine Monitoring Be Recommended?

OBJECTIVES: To determine the percentage of detectable tobramycin troughs and acute kidney injury in critically ill children without cystic fibrosis on inhaled therapy. DESIGN: Historic cohort. SETTING: Academic hospital. PATIENTS: Forty children less than 18 years receiving inhaled tobramycin across 6.5 years. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary objective was to determine the percentage of detectable tobramycin troughs greater than or equal to 0.5 µg/mL. Secondary objectives included a comparison of acute kidney injury in children with and without detectable troughs. Twenty-two (55%) had trough concentrations obtained. Ten of these (45.5%) had detectable concentrations, with a median of 0.85 µg/mL (interquartile range, 0.5-2.0). There was no statistical significance between the detectable and nondetectable groups in age, gender, and method of administration. However, patients in the detectable group tended to be younger than nondetectable group and more likely to have a tracheotomy. There was a clinically significant decrease in estimated glomerular filtration rate in the detectable trough group. CONCLUSIONS: Detectable troughs were noted in almost half of patients with concentrations obtained. A clinically significant decrease in estimated glomerular filtration rate was noted in patients with detectable concentrations. Continued work should be directed to better understand outcomes and monitoring in children requiring inhaled tobramycin.

Pharmacokinetics and safety of an 8 week continuous treatment with once-daily versus twice-daily inhalation of tobramycin in cystic fibrosis patients.

OBJECTIVES: We evaluated the pharmacokinetics, safety and tolerability of two different continuous treatment regimens of tobramycin inhalation solution (TIS) in 29 cystic fibrosis (CF) patients chronically infected with Pseudomonas aeruginosa. PATIENTS AND METHODS: In this randomized, multicentre, open-label, two-period crossover study, TIS (300 mg/5 mL) was administered via PARI eFlow(®) rapid once daily and twice daily each for 8 weeks. Serum pharmacokinetics of these two regimens was analysed. Tobramycin levels were determined before the morning dose and at 30, 60 and 90 min after the end of nebulization in the middle and at the end of each 8 week cycle. At these timepoints, trough and peak serum tobramycin concentrations (Cmax, mg/L) as well as the area under the curve for 0-90 min of tobramycin (AUC0-90min) were assessed in order to evaluate the risk of systemic toxicity. Safety parameters and forced expiratory volume in 1 s (FEV1) were assessed. RESULTS: For once-daily treatment, tobramycin levels were 10% higher after 8 weeks compared with 4 weeks (AUC0-90min ratio = 1.096, 90% CI = 0.860-1.396, P = 0.5237). For twice-daily treatment, tobramycin levels after 8 weeks showed a 40% decrease compared with 4 weeks (AUC0-90min ratio = 0.608, 90% CI = 0.461-0.802, P = 0.0055). The AUC0-90min ratio at 8 weeks (once daily versus twice daily) did not differ significantly (AUC0-90min ratio = 0.749, 90% CI = 0.514-1.092, P = 0.2009). The mean FEV1 did not differ markedly compared between treatment periods or with baseline. No audiological or nephrotoxic side effects were noted. CONCLUSIONS: Continuous treatment with TIS (once daily or twice daily) over 8 weeks appears to be safe and tolerable.

Acute Kidney Injury With Tobramycin-Impregnated Bone Cement Spacers in Prosthetic Joint Infections.

BACKGROUND: Antibiotic-impregnated bone cement spacer (ACS) with tobramycin ± vancomycin is commonly used in a 2-stage replacement of infected prosthetic joints. This procedure has been associated with development of acute kidney injury (AKI). OBJECTIVE: To determine the incidence and risk factors for AKI after implantation of tobramycin-impregnated ACS. METHODS: This prospective, observational study evaluated 50 consecutive patients who received tobramycin ACS for first-stage revision of an infected hip or knee arthroplasty from August 2011 to February 2013. AKI was defined as 50% or greater rise in serum creatinine (SCr) from baseline within the first 7 postoperative days (PODs). RESULTS: The incidence of AKI was 20%, with median onset occurring at POD 2 (interquartile range [IQR] = 1-3); patients with AKI had a longer median duration of hospital stay (16 days, IQR = 12-17, vs 10 days, IQR = 8-10; P = 0.03). Serum tobramycin concentrations were significantly higher in the AKI group, peaking on POD 1 (median 1.9 vs 0.9 µg/mL, P = 0.01). Risk factors for nephrotoxicity identified by multivariate analysis were use of bone cement premanufactured with gentamicin (OR = 8.2; 95% CI = 1.1-60; P = 0.04), administration of blood transfusions intraoperatively (OR = 32.5; 95% CI = 2.3-454.3; P = 0.01) and nonsteroidal anti-inflammatory drugs postoperatively (OR = 23.0; 95% CI = 1.3-397.7; P = 0.03). CONCLUSIONS: Tobramycin ACS is associated with a high risk of AKI. Measures to minimize AKI risk in the perioperative period include early detection through close monitoring of SCr, avoiding use of premanufactured bone cement containing gentamicin, and avoiding potential nephrotoxins within the first 72 hours postoperatively.

Acute renal failure after high-dose antibiotic bone cement: case report and review of the literature.

High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected.

Standard operating procedures for antibiotic therapy and the occurrence of acute kidney injury: a prospective, clinical, non-interventional, observational study.

INTRODUCTION: Acute kidney injury (AKI) occurs in 7% of hospitalized and 66% of Intensive Care Unit (ICU) patients. It increases mortality, hospital length of stay, and costs. The aim of this study was to investigate, whether there is an association between adherence to guidelines (standard operating procedures (SOP)) for potentially nephrotoxic antibiotics and the occurrence of AKI. METHODS: This study was carried out as a prospective, clinical, non-interventional, observational study. Data collection was performed over a total of 170 days in three ICUs at Charité - Universitaetsmedizin Berlin. A total of 675 patients were included; 163 of these had therapy with vancomycin, gentamicin, or tobramycin; were >18 years; and treated in the ICU for >24 hours. Patients with an adherence to SOP >70% were classified into the high adherence group (HAG) and patients with an adherence of <70% into the low adherence group (LAG). AKI was defined according to RIFLE criteria. Adherence to SOPs was evaluated by retrospective expert audit. Development of AKI was compared between groups with exact Chi2-test and multivariate logistic regression analysis (two-sided P <0.05). RESULTS: LAG consisted of 75 patients (46%) versus 88 HAG patients (54%). AKI occurred significantly more often in LAG with 36% versus 21% in HAG (P = 0.035). Basic characteristics were comparable, except an increased rate of soft tissue infections in LAG. Multivariate analysis revealed an odds ratio of 2.5-fold for LAG to develop AKI compared with HAG (95% confidence interval 1.195 to 5.124, P = 0.039). CONCLUSION: Low adherence to SOPs for potentially nephrotoxic antibiotics was associated with a higher occurrence of AKI. TRIAL REGISTRATION: Current Controlled Trials ISRCTN54598675. Registered 17 August 2007.

Evaluation of moxifloxacin 0.5% in treatment of nonperforated bacterial corneal ulcers: a randomized controlled trial.

PURPOSE: To compare the equivalence of moxifloxacin 0.5% with a combination of fortified cefazolin sodium 5% and tobramycin sulfate 1.3% eye drops in the treatment of moderate bacterial corneal ulcers. DESIGN: Randomized, controlled, equivalence clinical trial. PARTICIPANTS AND CONTROLS: Microbiologically proven cases of bacterial corneal ulcers were enrolled in the study and were allocated randomly to 1 of the 2 treatment groups. INTERVENTION: Group A was given combination therapy (fortified cefazolin sodium 5% and tobramycin sulfate) and group B was given monotherapy (moxifloxacin 0.5%). MAIN OUTCOME MEASURES: The primary outcome variable for the study was percentage of the ulcers healed at 3 months. The secondary outcome variables were best-corrected visual acuity and resolution of infiltrates. RESULTS: Of a total of 224 patients with bacterial keratitis, 114 patients were randomized to group A, whereas 110 patients were randomized to group B. The mean ± standard deviation ulcer size in groups A and B were 4.2 ± 2 and 4.41 ± 1.5 mm, respectively. The prevalence of coagulase-negative Staphylococcus (40.9% in group A and 48.2% in group B) was similar in both the study groups. A complete resolution of keratitis and healing of ulcers occurred in 90 patients (81.8%) in group A and 88 patients (81.4%) in group B at 3 months. The observed percentage of healing at 3 months was less than the equivalence margin of 20%. Worsening of ulcer was seen in 18.2% cases in group A and in 18.5% cases in group B. Mean time to epithelialization was similar, and there was no significant difference in the 2 groups (P = 0.065). No serious events attributable to therapy were reported. CONCLUSIONS: Corneal healing using 0.5% moxifloxacin monotherapy is equivalent to that of combination therapy using fortified cefazolin and tobramycin in the treatment of moderate bacterial corneal ulcers. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.