Is there a multinational consensus of tobramycin prescribing and monitoring for cystic fibrosis? Survey of current therapeutic drug monitoring practices in USA/Canada, UK/Ireland, and Australia/New Zealand.

OBJECTIVES: Sophisticated scientific methods have facilitated dose individualisation with substantial advancements in therapeutic drug monitoring (TDM) practice. It is unclear whether these methods have translated to the clinical setting. This study aimed to determine current TDM practice for tobramycin monitoring in cystic fibrosis (CF) centres in the USA and Canada, UK and Ireland, and Australia and New Zealand due to a high prevalence of CF. METHODS: A web-based survey was developed and circulated via CF specialist groups within the targeted geographical regions. Themes included centre demographics, tobramycin usage, dosing and infusion practices, TDM practices, and blood sampling methods. RESULTS: In total 77 responses were received from 75 different CF centres over the 3-month evaluation period (October 2019-January 2020). Respondents were from the USA and Canada (60%), Australia and New Zealand (25%), and the UK and Ireland (15%). Tobramycin was used in 97% of sites, with an international variation in practice across all survey aspects including dosing and infusion practice. TDM-based dose adjustment in the UK and Ireland was most commonly based only on trough sample collection for avoidance of toxicity, where use of computer programs for targeting both efficacy and toxicity endpoints were most common in Australia and New Zealand. The underlying pharmacokinetic basis of that program was not known by 33% of sites who utilised a computer program for tobramycin dose individualisation. CONCLUSION: There remains substantial heterogeneity in tobramycin management worldwide. Despite two decades of research into TDM of tobramycin, there has been a slow uptake of new technologies and evolution of practice. An improved understanding of TDM processes is required for translation of evidence-based research into clinical practice. International guidelines require updating due to the advances in research to support confidence in the changes in clinical practice.

Labelling Conventions and Product Package Insert of Parenteral Polymyxins: Factors Causing Potential Medication Errors and Impeding Optimal Clinical Use.

Two different labelling conventions for the contents of colistin methanesulfonate (i.e. colistin base activity [CBA] and international unit [IU]) are used in different parts of the world, and have caused prescribing errors and patient safety issues. This chapter discusses the key issues on the conversion between CBA and IU, and highlights that in pharmacokinetic analyses only the absolute mass of the chemical colistin methanesulfonate should be employed, but not the CBA or IU values. The scientific evidence is unknown for the limits specified for the pharmacopeial standards of the major components of colistin methanesulfonate and polymyxin B. The package information of parenteral colistin methanesulfonate in Europe has now been significantly improved by incorporating the latest pharmacokinetic/pharmacodynamic data. However, the current package information of almost all different brands of parenteral polymyxin B products is substantially out of date without solid pharmacological data. Updating the package information of different products of both polymyxins requires the coordination between major regulatory authorities and will significantly facilitate the optimisation of their use in patients.

What is the best method for measuring renal function in adults and children with cystic fibrosis?

AIMS: To measure the glomerular filtration rate (GFR) in adults and children with cystic fibrosis (CF) using a radio-isotope technique as the gold standard and to compare this to serum creatinine based equations, serum cystatin C levels and tobramycin clearance, and to determine which method correlates most closely with measured GFR in this population.

Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models.

Colistin is increasingly used as last-line therapy against Gram-negative pathogens. The pharmacokinetic (PK)/pharmacodynamic (PD) index that best correlates with the efficacy of colistin remains undefined. The activity of colistin against three strains of Pseudomonas aeruginosa was studied in neutropenic mouse thigh and lung infection models. The PKs of unbound colistin were determined from single-dose PK studies together with extensive plasma protein binding analyses. Dose-fractionation studies were conducted over 24 h with a dose range of 5 to 160 mg/kg of body weight/day. The bacterial burden in the thigh or lung was measured at 24 h after the initiation of treatment. Relationships between antibacterial effect and measures of exposure to unbound (f) colistin (area under the concentration-time curve [fAUC/MIC], maximum concentration of drug in plasma [fC(max)]/MIC, and the time that the concentration in plasma is greater than the MIC [fT > MIC]) were examined by using an inhibitory sigmoid maximum-effect model. Nonlinearity in the PKs of colistin, including its plasma protein binding, was observed. The PK/PD index that correlated best with its efficacy was fAUC/MIC in both the thigh infection model (R(2) = 87%) and the lung infection model (R(2) = 89%). The fAUC/MIC targets required to achieve 1-log and 2-log kill against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, while the corresponding values were 12.2 to 16.7 and 36.9 to 45.9 in the lung infection model. The findings of this in vivo study indicate the importance of achieving adequate time-averaged exposure to colistin. The results will facilitate efforts to define the more rational design of dosage regimens for humans.

Renal dysfunction in cystic fibrosis: is there cause for concern?

Most people associate cystic fibrosis (CF) with lung disease. Although this is the major cause of morbidity and mortality, CF is in fact a multi-organ disease. Patients with CF are living longer. Accompanying their increased life expectancy are complications not previously encountered. One of the less obvious concerns is that of renal dysfunction associated with long-term exposure to aminoglycosides as well as renally toxic immunosuppressants in lung transplant recipients. This article reviews what is known about the extent of the problem, summarizes what the current practices of measuring and monitoring renal function in patients with CF, and makes suggestions for alternative approaches. In particular, the potential role of cystatin C will be discussed.

Renal disposition of colistin in the isolated perfused rat kidney.

Nephrotoxicity is an important limitation to the clinical use of colistin against Pseudomonas aeruginosa and other gram-negative pathogens. Previous work reported net tubular reabsorption of colistin by the kidney in vivo, but there is no knowledge of its disposition within the kidney. This study investigated the renal disposition and potential transport mechanisms of colistin in the isolated perfused rat kidney (IPK) model by perfusing with colistin sulfate alone (2 microg/ml) or in the presence of potential inhibitors (tetraethylammonium [TEA], glycine-glycine [Gly-Gly], or hydrochloric acid [HCl]) at three different concentrations. When perfused alone, the renal clearances (CL(R)) for colistin A and B (the major components of colistin) in control kidneys were constant and low (mean values < 0.05 ml/min throughout the perfusion). The mean clearance ratios [CR, defined as CL(R)/(f(u) x GFR), where f(u) is the fraction of drug unbound in perfusate and GFR is the glomerular filtration rate] were significantly less than 1. It was concluded that there is net tubular reabsorption of colistin, and this exceeded the reabsorption of water. Less than 10% eliminated from perfusate was recovered in urine, suggesting considerable renal accumulation of colistin. The CR values for colistin were significantly increased when perfused with TEA (500 microM), Gly-Gly (833 microM), and HCl (2,500, 5,000, and 10,000 microM). It is proposed that renal reabsorption of colistin may involve organic cation transporters (inhibited by TEA) and peptide transporters (inhibited by Gly-Gly) and that the process is sensitive to the pH of urine.

Stability of colistin methanesulfonate in pharmaceutical products and solutions for administration to patients.

Colistin methanesulfonate (CMS) has the potential to hydrolyze in aqueous solution to liberate colistin, its microbiologically active and more toxic parent compound. While conversion of CMS to colistin in vivo is important for bactericidal activity, liberation of colistin during storage and/or use of pharmaceutical formulations may potentiate the toxicity of CMS. To date, there has been no information available regarding the stability of CMS in pharmaceutical preparations. Two commercial CMS formulations were investigated for stability with respect to colistin content, which was measured by a specific high-performance liquid chromatography method. Coly-Mycin M Parenteral (colistimethate lyophilized powder) was stable (<0.1% of CMS present as colistin) for at least 20 weeks at 4 degrees C and 25 degrees C at 60% relative humidity. When Coly-Mycin M was reconstituted with 2 ml of water to a CMS concentration of 200 mg/ml for injection, Coly-Mycin M was stable (<0.1% colistin formed) for at least 7 days at both 4 degrees C and 25 degrees C. When further diluted to 4 mg/ml in a glucose (5%) or saline (0.9%) infusion solution as directed, CMS hydrolyzed faster at 25 degrees C (<4% colistin formed after 48 h) than at 4 degrees C (0.3% colistin formed). The second formulation, CMS Solution for Inhalation (77.5 mg/ml), was stable at 4 degrees C and 25 degrees C for at least 12 months, as determined based on colistin content (<0.1%). This study demonstrated the concentration- and temperature-dependent hydrolysis of CMS. The information provided by this study has important implications for the formulation and clinical use of CMS products.

Comparison of once-, twice- and thrice-daily dosing of colistin on antibacterial effect and emergence of resistance: studies with Pseudomonas aeruginosa in an in vitro pharmacodynamic model.

OBJECTIVES: The optimal dosing regimen for colistin methanesulphonate (CMS) against Pseudomonas aeruginosa is unknown. CMS is converted in vivo to its active form, colistin. We evaluated three colistin dosage regimens in an in vitro pharmacokinetic/pharmacodynamic model. METHODS: Three intermittent dosage regimens involving 8, 12 and 24 h dosage intervals (Cmax of 3.0, 4.5 or 9.0 mg/L, respectively) were employed. Antibacterial activity and emergence of resistance were investigated over 72 h using two strains of P. aeruginosa: ATCC 27853 and 19056. The areas under the killing curves (AUBC(0-72)) and population analysis profiles (AUCPAP) were used to compare regimens. RESULTS: No difference in bacterial killing was observed among different regimens. For ATCC 27853, substantial killing was observed after the first dose with less killing after subsequent doses irrespective of regimen; regrowth to between 5.95 and 7.49 log10 cfu/mL occurred by 72 h (growth control 7.46 log10 cfu/mL). AUCPAPs at 72 h for the 12 hourly (4.08 +/- 1.54) and 24 hourly (4.16 +/- 2.48) regimens were substantially higher than that for both the growth control (1.63 +/- 0.08) and 8 hourly regimen (2.30 +/- 0.87). For 19056, bacterial numbers at 72 h with each regimen (1.32-2.75 log10 cfu/mL) were far below that of the growth control (7.79 log10 cfu/mL); AUCPAPs could not be measured effectively due to the substantial killing. CONCLUSIONS: No difference in overall bacterial kill was observed when the recommended maximum daily dose was administered at 8, 12 or 24 h intervals. However, the 8 hourly regimen appeared most effective at minimizing emergence of resistance.

Subacute toxicity of colistin methanesulfonate in rats: comparison of various intravenous dosage regimens.

The relative nephro- and neurotoxicity of colistin methanesulfonate (CMS) was investigated with rats during 7 days of intravenous administration in regimens mimicking twice- and once-daily dosing of a clinically relevant dose for humans. Histological examination revealed more-severe renal lesions with the regimen corresponding to once-daily dosing, indicating that the potential for renal toxicity may be greater with extended-interval dosing.

Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis--caution with trough concentrations.

BACKGROUND: : Once daily intravenous aminoglycoside dosing (ODD) is widely used to treat acute Pseudomonas aeruginosa exacerbations in patients with cystic fibrosis. Controversy exists as to what is the most appropriate method of therapeutic drug monitoring (TDM) of such therapy with recommendations including trough plasma concentrations of <1 mg/L or <2 mg/L, area under curve (AUC) and various nomograms. This study aimed to compare the exposures to ODD of tobramycin in adults and children with cystic fibrosis using the AUC and trough TDM approaches. METHODS: : Using a mono-exponential software program to calculate AUC from 2 plasma concentrations, AUCs were determined in 22 adults with pre-dose tobramycin concentrations <1 mg/L. The exposure of 5 children with reduced tobramycin clearances was simulated at the usual recommended dose of 10 mg/kg/daily but retaining a trough <1 mg/L. RESULTS: : A tobramycin dose of 10 mg/kg of tobramycin in these patients with normal serum creatinine and a trough concentration <1 mg/L resulted in exposures in excess of those associated with conventional 8-hourly dosing. CONCLUSIONS: : The TDM approach of a trough <1 mg/L, as used with conventional 8-hourly tobramycin dosing, is not relevant to ODD.

Community use of intranasal midazolam for managing prolonged seizures.

BACKGROUND: Until a few years ago, rectal diazepam (RD) was the only option available to parents and carers managing prolonged seizures. However, its use in the community was limited due to the requirement for privacy, and because education staff in South Australia are not permitted to carry out invasive procedures. METHOD: Following a literature review, a seizure management training package was developed to enhance the implementation of a trial treatment protocol for the administration of intranasal midazolam (INM). Parents, carers and education staff were later surveyed about their experiences and perceptions. RESULTS: Intranasal midazolam was administered to 131 people (51 children and 80 adults), with 96.9% control of seizures, and only one minor adverse event. Parents expressed a preference for INM over RD because of the shorter time it took to take effect and wear off, and the ability to administer it in public if necessary. CONCLUSION: Intranasal midazolam is a safe and practical alternative to rectal diazepam for managing prolonged seizures in the community.

Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections.

Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago. We summarise recent progress in understanding the complex chemistry, pharmacokinetics, and pharmacodynamics of colistin, the interplay between these three aspects, and their effect on the clinical use of this important antibiotic. Recent clinical findings are reviewed, focusing on evaluation of efficacy, emerging resistance, potential toxicities, and combination therapy. In the battle against rapidly emerging bacterial resistance we can no longer rely entirely on the discovery of new antibiotics; we must also pursue rational approaches to the use of older antibiotics such as colistin.

Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria.

Infections caused by multi-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa, are increasing worldwide. In patients with cystic fibrosis (CF), resistance in P. aeruginosa to numerous anti-pseudomonal agents is becoming common. The absence since 1995, of new substances active against resistant Gram-negative bacteria, has caused increasing concern. Colistin, an old antibiotic also known as polymyxin E, has attracted more interest recently because of its significant activity against multi-resistant P. aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, and the low resistance rates to it. Because its use as an anti-pseudomonal agent was displaced by the potentially less toxic aminoglycosides in 1970s, our knowledge of this drug is limited. However, there has been a significant recent increase in the data gathered on colistin, focussing on its chemistry, antibacterial activity, mechanism of action and resistance, pharmacokinetics, pharmacodynamics and new clinical application. It is likely that colistin will be an important antimicrobial option against multi-resistant Gram-negative bacteria, for some years to come.

Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate.

OBJECTIVES: To determine the disposition of colistin methanesulphonate (CMS) and colistin following intravenous (iv) administration of CMS in rats. METHODS: Five rats received a single iv bolus of 15 mg/kg CMS. Plasma concentrations of CMS and of colistin formed by the hydrolysis of CMS were determined by HPLC. The pharmacokinetic parameters of CMS and colistin were calculated using non-compartmental analysis. RESULTS: Total body clearance, volume of distribution at steady state and terminal half-life of CMS averaged 11.7 mL/min/kg, 299 mL/kg and 23.6 min, respectively. The mean terminal half-life of colistin was 55.7 min. Approximately 60% of the dose was eliminated via the urine in 24 h and presented as a mixture of CMS and colistin. CONCLUSIONS: Colistin appeared in plasma soon after administration of CMS, indicating rapid conversion of CMS into colistin. CMS had a shorter terminal half-life than did colistin, indicating that the disposition of the colistin generated from CMS was rate-limited by its elimination. Most of the dose was recovered in urine, half in the form of colistin. The high percentage of colistin recovered in urine was believed to be formed by hydrolysis of CMS in the bladder and in the collection vessel, and/or conversion from CMS in the kidney.

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.

Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis.

OBJECTIVES: To define the steady-state pharmacokinetics of colistin methanesulphonate and colistin in patients with cystic fibrosis (CF) following intravenous administration of the former. MATERIALS AND METHODS: The study was conducted in 12 patients with CF following intravenous administration of colistin methanesulphonate (1.63-3.11 mg/kg) every 8 h for at least 2 days. On the day of study, four blood samples were collected from each patient at 60, 120, 240 and 360 min after the end of the infusion. Concentrations of colistin methanesulphonate and colistin in plasma were measured separately by HPLC. RESULTS: At steady-state, colistin methanesulphonate had a mean (+/- S.D.) total body clearance, volume of distribution and half-life of 2.01 +/- 0.46 mL/min per kg, 340 +/- 95 mL/kg and 124 +/- 52 min, respectively. Colistin had a significantly longer mean half-life of 251 +/- 79 min (P<0.001). With the regimen used, colistin methanesulphonate was well tolerated. This is the first report on the pharmacokinetics of colistin methanesulphonate in CF patients determined using concentrations of colistin methanesulphonate and colistin in plasma. CONCLUSIONS: Based on the in vitro pharmacodynamics against Pseudomonas aeruginosa previously published by our group and these pharmacokinetic findings, dose escalating trials may be warranted to maximize efficacy.

Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration.

The pharmacokinetics of colistin was investigated using specific high-performance liquid chromatography (HPLC) to measure the concentrations of colistin and colistin A and B in plasma and urine in five rats after administration of an intravenous bolus of 1 mg of colistin sulfate/kg of body weight. There were differences in the pharmacokinetic behaviors of unbound colistin A and B. This is the first report of the use of HPLC to study the pharmacokinetics of colistin and its two major components.

Stability of colistin and colistin methanesulfonate in aqueous media and plasma as determined by high-performance liquid chromatography.

The stabilities of colistin and colistin methanesulfonate (CMS) in different aqueous media were studied by specific high-performance liquid chromatography (HPLC) methods. Colistin was stable in water at 4 and 37 degrees C for up to 60 days and 120 h, respectively. However, degradation was observed when colistin was stored in isotonic phosphate buffer (0.067 M, pH 7.4) and human plasma at 37 degrees C. The stability of CMS from three different sources in water was explored by strong-anion-exchange (SAX) HPLC for CMS and by measuring the concentrations of colistin formed from the hydrolysis of CMS. The peaks of CMS in SAX HPLC disappeared almost completely after 12 h at 37 degrees C, but appeared to remain intact for up to 2 days at 4 degrees C. Over the same period, there was no formation of colistin at 4 degrees C. In water, phosphate buffer, and plasma, there was rapid formation of colistin within 24 to 48 h at 37 degrees C from the three sources of CMS. The hydrolysis products were assumed to be a complex mixture of many different sulfomethyl derivatives, including colistin. The stability of a fourth source of CMS in Mueller-Hinton broth examined during 30 min at 37 degrees C revealed no formation of colistin. Along with previous microbiological studies, this suggested that different sulfomethyl CMSs possess intrinsic antibacterial activity. These results will be helpful for understanding the pharmacokinetics and pharmacodynamics of colistin and CMS in humans and animals.