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In this review, we report the available data regarding efficacy, safety and pharmacokinetics of colistin in the treatment of multidrug-resistant Gram-negative bacteria in neonates and infants. Seventeen clinical studies, involving 312 patients, and 3 pharmacokinetics studies were identified. Blood stream infection was the most common source of infection, followed by pneumonia and meningitis/ventriculitis. In most cases, colistin was administered in association with other antibiotics. The most common route of administration was intravenous, with colistimethate doses ranging from 25,000 to 225,000 IU/kg/day divided into 2 or 3 doses. A recent pharmacokinetic study suggested that the appropriate intravenous dose should be >150,000 IU/kg/day. Microbiologic cure was obtained in 94.2% of patients and survival was 76.6%. The combination of intraventricular and intravenous colistin should be used in meningitis/ventriculitis. Nebulized colistin should be used as adjunctive treatment, but not as monotherapy. Nephrotoxicity and apnea were reported in 5.8% and 3.9% of patients respectively.The use of colistin for multidrug-resistant Gram-negative infections in neonates and infants is effective and safe, but the quality of studies is moderate. The optimal intravenous dose should be higher than that indicated in most reports.

Rationale: The potential of azithromycin to alter the antimicrobial and clinical benefits of inhaled tobramycin in patients with cystic fibrosis (CF) has been previously reported. The potential interaction between azithromycin and intravenous antibiotics in the treatment of pulmonary exacerbations is unknown. Objectives: To determine if chronic azithromycin use as a concomitant therapy is associated with change in lung function after receiving intravenous antibiotic regimens including tobramycin or colistimethate. Methods: This was a retrospective cohort study evaluating the association of azithromycin with intravenous tobramycin or colistimethate in adult patients with CF treated for a pulmonary exacerbation. The primary outcome was relative lung function recovery (forced expiratory volume in 1 s [FEV(1)]) after exacerbation treatment. Generalized estimating equations were applied to account for repeated events with independent correlation structures and robust standard errors, incorporating several confounders. Results: A total of 220 exacerbation events occurred in 121 patients in the tobramycin group (47% using azithromycin), and 207 exacerbation events occurred in 86 patients in the colistimethate group (59% using azithromycin). Azithromycin use was associated with less FEV(1)% recovery in patients treated with tobramycin (−3% relative FEV(1)% recovery [95% confidence interval (CI), −7 to 0.2] and −2.64% absolute FEV(1)% change [95% CI, −4.52 to −0.76]). Azithromycin use was associated with greater recovery of FEV(1)% when treated with colistimethate (+3% relative FEV(1)% recovery [95% CI, −0.1 to 7] and 2.00% absolute improvement in FEV(1)% [95% CI, 0.13 to 3.87]). The odds of 90% or 100% recovery to baseline FEV(1)% were lower with azithromycin use in the tobramycin cohort and higher with azithromycin use in the colistimethate cohort but were not statistically significant. Conclusions: Azithromycin use was associated with a more favorable response in adult patients with CF treated with intravenous colistimethate but a less favorable response in those treated with intravenous tobramycin.

Background Intravenous colistin is widely used to treat infections in pediatric patients. Unfortunately, there is a paucity of pharmacological information to guide the selection of dosage regimens. The daily dose recommended by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) is the same body weight–based dose traditionally used in adults. The aim was to increase our understanding of the patient factors that influence the plasma concentration of colistin, and assess the likely appropriateness of the FDA and EMA dosage recommendations. Methods There were 5 patients, with a median age of 1.75 (range 0.1–6.25) years, a median weight of 10.7 (2.9–21.5) kg, and a median creatinine clearance of 179 (44–384) mL/min/1.73m2, who received intravenous infusions of colistimethate each 8 hours. The median daily dose was 0.21 (0.20–0.21) million international units/kg, equivalent to 6.8 (6.5–6.9) mg of colistin base activity per kg/day. Plasma concentrations of colistimethate and formed colistin were subjected to population pharmacokinetic modeling to explore the patient factors influencing the concentration of colistin. Results The median, average, steady-state plasma concentration of colistin (Css,avg) was 0.88 mg/L; individual values ranged widely (0.41–3.50 mg/L), even though all patients received the same body weight–based daily dose. Although the daily doses were ~33% above the upper limit of the FDA- and EMA-recommended dose range, only 2 patients achieved Css,avg ≥2mg/L; the remaining 3 patients had Css,avg Conclusions The FDA and EMA dosage recommendations may be suboptimal for many pediatric patients. Renal functioning is an important determinant of dosing in these patients.

Background Nephrotoxicity is a known adverse effect of polymyxin antibiotics, including colistin. Although previous meta-analyses have aimed to characterize colistin-associated nephrotoxicity risk relative to other antibiotics, included studies were observational in nature with high risk of confounding and heterogeneity. We conducted this systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to evaluate the incidence of nephrotoxicity associated with colistin versus minimally nephrotoxic antibiotics. Methods We searched PubMed, EMBASE, Cochrane Library, and 3 trial registries for RCTs comparing the nephrotoxicity of colistin to nonpolymyxin antibiotics. Randomized controlled trials that used aminoglycosides were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The study outcome was the rate of nephrotoxicity. Results Five RCTs with a total of 377 patients were included. Most patients received colistin for pneumonia in the intensive care unit, and the comparators were β-lactam-based regimens. Colistimethate sodium was dosed at 9 million units/day (300 mg/day of colistin base activity), with administration of a loading dose in 4 studies. The nephrotoxicity incidence in patients who received colistin was 36.2% (95% CI, 23.3% to 51.3%). The nephrotoxicity rate was significantly higher in the colistin arm than comparators (RR, 2.40; 95% CI, 1.47 to 3.91; P ≤ .001; I2 = 0%), and the number needed to harm was 5. Findings persisted upon one-study-removed-analysis. Conclusions This meta-analysis of RCTs found a colistin-associated nephrotoxicity rate of 36.2% and an increase in this risk compared with β-lactam-based regimens by 140%. Colistin should be regarded as a last-line agent and safer alternatives should be considered when possible., In this meta-analysis of randomized controlled trials, colistin was associated with a nephrotoxicity rate of 36%. Nephrotoxicity risk was 140% higher with colistin compared to a beta-lactam-based regimen.

Background Determining a suitable dose of intravenous colistimethate is challenging because of complicated pharmacokinetics, confusing terminology, and the potential for renal toxicity. Only recently have reliable pharmacokinetic/pharmacodynamic data and dosing recommendations for intravenous colistimethate become available. Objective The aim of this work was to develop a clinician-friendly, easy-to-use mobile app incorporating up-to-date dosing recommendations for intravenous colistimethate in critically ill adult patients. Methods Swift programming language and common libraries were used for the development of an app, ColistinDose, on the iPhone operating system (iOS; Apple Inc). The compatibility among different iOS versions and mobile devices was validated. Dosing calculations were based on equations developed in our recent population pharmacokinetic study. Recommended doses generated by the app were validated by comparison against doses calculated manually using the appropriate equations. Results ColistinDose provides 3 major functionalities, namely (1) calculation of a loading dose, (2) calculation of a daily dose based on the renal function of the patient (including differing types of renal replacement therapies), and (3) retrieval of historical calculation results. It is freely available at the Apple App Store for iOS (version 9 and above). Calculated doses accurately reflected doses recommended in patients with varying degrees of renal function based on the published equations. ColistinDose performs calculations on a local mobile device (iPhone or iPad) without the need for an internet connection. Conclusions With its user-friendly interface, ColistinDose provides an accurate and easy-to-use tool for clinicians to calculate dosage regimens of intravenous colistimethate in critically ill patients with varying degrees of renal function. It has significant potential to avoid the prescribing errors and patient safety issues that currently confound the clinical use of colistimethate, thereby optimizing patient treatment.

Objectives The aim of this study was to assess colistin use in a country endemic for multidrug-resistant Gram-negative bacteria (MDR-GNB). Methods Colistin prescription patterns were evaluated in 22 Italian centres. Factors associated with use of colistin in combination with other anti-MDR-GNB agents were also assessed. Results A total of 221 adults receiving colistin were included in the study. Their median age was 64 years (interquartile range 52–73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly for targeted therapy (168/221; 76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenous colistin was administered in combination with at least another anti-MDR-GNB agent in 80% of cases (163/203). A loading dose of 9 MU of colistimethate was administered in 79% of patients receiving i.v. colistin and adequate maintenance doses in 85%. In multivariable analysis, empirical therapy [odds ratio (OR) = 3.25, 95% confidence interval (CI) 1.24–8.53;P = 0.017] and targeted therapy for carbapenem-resistant Enterobacterales infection (OR = 4.76, 95% CI 1.69–13.43; P = 0.003) were associated with use of colistin in combination with other agents, whilst chronic renal failure (OR = 0.39, 95% CI 0.17–0.88; P = 0.024) was associated with use of colistin monotherapy. Conclusion Colistin remains an important option for severe MDR-GNB infections when other treatments are not available. Despite inherent difficulties in optimising its use owing to peculiar pharmacokinetic/pharmacodynamic characteristics, colistin was mostly used appropriately in a country endemic for MDR-GNB.

Objectives To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Patients and methods Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. Results Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable ( Conclusions In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

The availability of sensitive, accurate and specific analytical methods for the measurement of polymyxins in biological fluids has enabled an understanding of the pharmacokinetics of these important antibiotics in healthy humans and patients. Colistin is administered as its inactive prodrug colistin methanesulfonate (CMS) and has especially complex pharmacokinetics. CMS undergoes conversion in vivo to the active entity colistin, but the rate of conversion varies from brand to brand and possibly from batch to batch. The extent of conversion is generally quite low and depends on the relative magnitudes of the conversion clearance and other clearance pathways for CMS of which renal excretion is a major component. Formed colistin in the systemic circulation undergoes very extensive tubular reabsorption; the same mechanism operates for polymyxin B which is administered in its active form. The extensive renal tubular reabsorption undoubtedly contributes to the propensity for the polymyxins to cause nephrotoxicity. While there are some aspects of pharmacokinetic behaviour that are similar between the two clinically used polymyxins, there are also substantial differences. In this chapter, the pharmacokinetics of colistin, administered as CMS, and polymyxin B are reviewed, and the therapeutic implications are discussed.

Clinical use of the polymyxin antibiotics began approximately 10 years after their discovery in the late 1940s. Their concentrations in biological fluids were measured using microbiological methods. These methods were reasonably accurate for measuring the active polymyxin base, such as polymyxin B and colistin (polymyxin E), but were used inappropriately for measuring the concentrations of “colistin” in humans or animals following the administration of colistimethate, also known as colistin methanesulphonate (CMS). The use of polymyxins for systemic infections waned in the 1970s because of their toxicity and the preference for other antibiotics, but their value for treating infections caused by several important Gram-negative pathogens becoming resistant to other antibiotics was realized in the mid-1990s. The lack of adequate pharmacokinetic and pharmacodynamic knowledge spurred the development of methods more specific for measuring polymyxin B and colistin after their administrations as sulphate salts, and of colistin and CMS after the administration of CMS sodium. These methods have been based on high-performance liquid chromatography, detection and quantification of fluorescent derivatives of the polymyxin bases, or of the bases themselves with detection and quantification by mass spectrometry.

All of the small number of studies conducted during the second half of last century to investigate the pharmacokinetics of polymyxins in animals used microbiological methods to quantify the compounds in biological fluids. Those methods generally lacked the accuracy and precision required for such investigations and, in the case of studies involving administration of colistin methanesulfonate (CMS), ongoing conversion to colistin during microbiological incubation of collected samples artifactually elevated the measured concentration of colistin. The pharmacokinetic studies reviewed in this chapter involved use of more accurate, precise and specific methods for the measurement of the relevant compounds in biological matrices. The studies have been conducted in a number of pre-clinical animal species following administration via various routes (e.g. intravenous, intrapulmonary), and have provided important insights into not only the global pharmacokinetics as viewed from plasma but also the tissue distribution and handling by key organs particularly the kidneys.

The purpose was to evaluate the clinical outcome in multi-drug resistant Pseudomonas aeruginosa (MDR-PA) bacterial keratitis and report the successful use of an alternative antibiotic, topical colistimethate in some of them. The medical records of 12 culture-proven MDR-PA keratitis patients, all exhibiting in vitro resistance by Kirby-Bauer disc diffusion method to ≥ three classes of routinely used topical antibiotics were reviewed. Eight patients were treated with 0.3% ciprofloxacin or ofloxacin, 1 patient with 5% imipenem/cilastatin and 3 patients with 1.6% colistimethate. The outcomes in 8 eyes treated with only fluoroquinolones were evisceration in 4 eyes, therapeutic corneal graft in 1 eye, phthisis bulbi in 1 eye, and no improvement in 2 eyes. The eye treated with imipenem/cilastin required a therapeutic corneal graft. All the three eyes treated with 1.6% colistimethate healed. Colistimethate may prove to be an effective alternative antibiotic in the treatment of MDR-PA keratitis.

We report the case of a patient with a history of chronic bronchiectasis that presented with new onset fatigue, shortness of breath, peripheral blood eosinophilia and infiltrates on chest radiograph. Eight days previously, she was prescribed inhaled colistimethate sodium 75 mg bid to prevent exacerbations of her respiratory condition. To our knowledge, our case is the first to show the clinical and radiologic features of inhaled-colistimethate-induced pulmonary eosinophilia. It also shows the rapid resolution of its features following treatment with oral corticosteroids. Eosinophilic lung reaction to inhaled colistin is rarely reported in the literature. Clinicians should be aware of this possible side effect.

Background The use of inhaled colistimethate in our population guaranteed a good antibacterial coverage in our patients. Purpose To analyse the use of inhaled colistimethate according to indication and prescribed dose, presence or absence of the infectious agent, as well as its alternation with other therapies. To evaluate the cost of treatment associated with each patient. Material and methods Retrospective 1 year observational study (January 2016 to January 2017) of patients treated with inhaled colistimethate. We analysed indication, prescribed dose, alternation with inhaled tobramycin, presence or absence of infectious agent, concomitant therapy with ciprofloxacin and associated inhalation therapy. Data were obtained from the Farmatools ® outpatients program and from the electronic medical history software Drago AE ® . Farmatools ® was used to estimate the cost of the treatments. Results Fifty-five patients were in treatment with colistimethate, of which 58.18% (32) were female. Mean patient age was 51.7 years (6–94). 58.18% of patients (32) had bronchiectasis, 29% (16) cystic fibrosis (CF), 7.27% (five) pseudomonas infection and 5. 45% (three) lung transplant. 92. 7% of patients (51) received a prescribed dose of 1 million IU/12 hours, 3.63% of patients (two) received 1 million IU/24 hours. Considering the isolated microorganism we found this incidence: 78.18% (43) pseudomonas aeruginosa, 3.63% (two) pseudomonas aeruginosa and staphylococcus aureus, 1.81% (one) pseudomonas aeruginosa and haemophylus influenzae, 1.81% (one) pseudomonas aeruginosa and acinetobacter baumannii, 1.81% (one) pseudomonas aeruginosa and mycobacterium avium. We found no isolated microorganism in 7.27% of patients. 12.7% of patients (seven) were also treated with inhaled tobramycin, all of them cystic fibrosis patients. 43.66% of patients (24) were also treated with ciprofloxacin, 10 patients throughout the year (all of them CF patients) and 14 with a mean duration of therapy of 10.5 days. 56.34% of patients (31) did not receive ciprofloxacin during their treatment with inhaled colistimethate. The total cost of colistimethate treatment was €1221.8 per year. The cost per patient was €2221.4/patient/year. Conclusion The most frequently isolated microorganism was pseudomonas aeruginosa. An issue to be evaluated would be the recommendation of ciprofloxacin as an adjuvant to colistimethate in CF, since it was not performed in all cases during the pharmaceutical care process in these patients. References and/or Acknowledgements Technical sheet colistimethate. No conflict of interest

WOS: 000439906200002 PubMed ID: 30035652 Objective: To investigate the molecular mechanisms of colistimethate sodium-induced nephrotoxicity and the protective effect of N-acetylcysteine (NAC) against nephrotoxicity.Methods: Twenty-eight Wistar rats were divided into four groups comprised of control, colistin, NAC, and colistin-NAC co-treatment, respectively. Serum creatinine and urine N-acetyl--d-glucosaminidase (NAG) levels were measured at different time intervals. Histological changes, apoptosis, total oxidant and antioxidant status, and the expression levels of endothelial nitric oxide synthase (eNOS), superoxide dismutase 2 (SOD2), and matrix metalloproteinase 3 (MMP3) were evaluated in renal tissue.Results: In the colistin group, post-treatment creatinine levels were higher than pretreatment levels (p=.001). There was a significant increase in urine NAG level following colistin treatment on day 10, compared to the baseline value and the first day of treatment (p=.001 and .0001, respectively). Urine NAG levels were higher in the colistin group on the 10th day of treatment than in the other groups (p

Colistin has re-emerged as an essential antibiotic for the treatment of carbapenem-resistant Gram-negative infections. Unfortunately, its utility is limited by high rates of nephrotoxicity, even at potentially therapeutic concentrations, and an overall lack of understanding on how to optimally administer the agent. In this review, recent advancements in the understanding of the safety and efficacy of colistin are discussed and strategies and suggestions on how to balance the two are described.

This article reviews mechanisms, incidences, risk factors and preventive modalities of colistin toxicity as well as colistin use in special populations and through special routes. All clinical studies that examined the pharmacokinetic/pharmacodynamic, efficacy and side effects of colistin in the management of multidrug-resistant organisms in different patient population including pediatrics, adults, obese, critically ill, burn or cancer patients with any route of drug administration were considered. Compared with older recommended doses, current dosing approach improves cure rate without significant increase in the rate of colistin-induced nephrotoxicity. Efficacy and safety of high doses of colistin should be considered in the future studies. Also comparing efficacy and safety of different doses of aerosolized colistin and defining the appropriate dose in different populations is another open area of future researches.

Background In 2010, aztreonam for inhalation solution joined aminoglycosides and colistimethate as a new cystic fibrosis (CF) chronic inhaled antimicrobial therapy. We studied how the introduction of this new inhaled antibiotic class changed the management of US CF patients. Methods The use of inhaled aminoglycosides, colistimethate, and aztreonam among patients followed in the CF Foundation Patient Registry was analyzed by age group, lung disease stage, and microbiologic status both annually, and at individual visits between 2009 and 2012. Results The overall prevalence of inhaled antibiotic use did not change during the period, but the prevalence of annual and any visit treatment with >1 inhaled antibiotic class more than doubled. Adults, those with advanced lung disease, and those with >1 Pseudomonas aeruginosa respiratory culture were more likely to receive >1 antibiotic class. Conclusions Inhaled antibiotic management of US CF patients has dramatically changed in association with the introduction of a third inhaled antibiotic class.

In the management of multidrug-resistant infections in critically ill patients with multiorgan dysfunction, consideration must be given to the pharmacokinetics and pharmacodynamics of an antimicrobial agent to optimize dosing. We describe a 25-year-old woman who was undergoing thrice-weekly hemodialysis and developed multidrug-resistant Pseudomonas aeruginosa bacteremia secondary to infected left and right ventricular assist devices. After multiple courses of antibiotics, her blood cultures revealed that the infecting organism was becoming progressively more resistant to antibiotic options. Cefepime 2 g administered over 3 hours/day (in combination with colistimethate) provided adequate drug levels for multidrug-resistant, cefepime-intermediate P. aeruginosa bacteremia in this patient. We present the clinical case of this patient, followed by a discussion of possible therapeutic approaches to be considered, including illustration of the principles of using extended-infusion antimicrobial regimens, and present the patient's resulting clinical course.

Objective: To assess the clinical and economic impact, in terms of reduction of costs associated with exacerbations, in a cohort of patients with non-cystic fibrosis (non-CF) BQ and PsA CBI treated with Promixin. Patients and Methods: A multicenter, observational, longitudinal prospective study of a cohort of adults with non-CF BQ and PsA CBI treated with Promixin. Data were collected in the year before and after nebulized treatment (pulmonary function, exacerbations without hospital admission, mean per pat/y and total number of admissions and per pat/y). Results: 86 pat, 45 males, 62±15 y. Results are shown in the following data table. Conclusions: Adherence to nebulized treatment is excellent in our patients. In clinical terms, this situation has allowed an improvement in lung function and a significant reduction in the number and severity of exacerbations and hospital admissions. Regarding this issue, the average cost per patient and year of treatment has been reduced by more than €1500 after onset of nebulized therapy.

Limited information is available on the urinary excretion of colistin in infected patients. This study aimed to investigate the pharmacokinetics of colistimethate sodium (CMS) and formed colistin in urine in patients with multidrug-resistant (MDR) Gram-negative bacterial infections. A pharmacokinetic study was conducted on 12 patients diagnosed with an infection caused by an extremely drug-resistant (XDR) P. aeruginosa strain and treated with intravenous CMS. Fresh urine samples were collected at 2-h intervals, and blood samples were collected predose ( C min ss ) and at the end of the CMS infusion ( C max ss ) for measurement of concentrations of CMS and formed colistin using high-performance liquid chromatography (HPLC). CMS urinary recovery was determined as the summed amount of CMS and formed colistin recovered in urine for each 2-h interval divided by the CMS dose. There were 12 enrolled patients, 9 of whom were male (75%). Data [median (range)] were as follows: age, 65.5 (37 to 86) years; colistimethate urinary recovery 0 to 6 h, 42.6% (2.9% to 72.8%); range of concentrations of colistin in urine, C min ss and C max ss of colistin in plasma, 0.9 (P. aeruginosa in our hospital. Future studies are warranted for optimizing CMS dosage regimens in urinary tract infection (UTI) patients.

We present the case of a 58-year-old woman who developed hypokalaemia and metabolic alkalosis 2 weeks after therapy with colistimethate sodium for the treatment of chronic lower limb ulcer infection by extensively drug-resistant (XDR) Pseudomonas aeruginosa. The metabolic changes observed resembled Bartter syndrome, a group of congenital disorders affecting the distal segments of the renal tubules. The metabolic abnormalities reversed spontaneously 6 days after drug discontinuation. Acquired forms of Bartter syndrome have been reported during courses of antibiotic therapy; however, to our knowledge, this is the first documented case associated with colistimethate therapy in an adult.

Colistin, the most widely used polymyxin antibiotic, was originally introduced in the late 1950s before the establishment of the present-day drug approval process. Originally shelved due to toxicity concerns, colistin, in the form of its inactive prodrug colistin methanesulfonate, has undergone a renaissance in the past 15 years. Unfortunately, this is not because of an improved adverse-effect profile but because colistin is among the only remaining antibiotics with activity against multidrug-resistant gram-negative bacilli. Pharmacokinetic and pharmacodynamic data are limited to guide the appropriate use of colistin; however, important advances have occurred over the past 5 years. Since its reintroduction, published reports regarding colistin have produced discordant results in terms of both efficacy and safety. Because the efficacy and toxicity of colistin are dose dependent, the impact of discordant dosing recommendations cannot be understated. This review highlights the issues leading to differing and often conflicting dosing recommendations, reviews the recent pharmacokinetic advances, and provides recommendations for the optimal use of colistin.

Despite many theoretical and in vitro advantages, clinical data comparing combination therapy with colistin + rifampicin to colistin alone for infection due to extremely-drug resistant (XDR) Acinetobacter baumanni are scarce and limited by small numbers and/or low quality evidence. This article represents the first large, randomized, controlled, prospective study comparing colistin monotherapy and combination therapy. The reviewed article found no difference in all cause or infection related mortality, though there was an improved rate of microbiological clearance in the combination therapy arm. This study adds important new data to the literature and sets the stage for future studies that can be designed to overcome the limitations of this study, which are discussed in detail below. Based on this study, we cannot say definitively that combination therapy is not warranted for treatment of invasive infection due to A. baumannii, but the results do suggest that rifampicin is not an ideal agent to be combined with colistin.

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

The drug of choice for treatment of Stenotrophomonas maltophilia is sulfamethoxazole/trimethoprim, and second-line therapy usually consists of a fluoroquinolone. However, in patients with glucose-6-phosphate dehydrogenase deficiency, neither sulfamethoxazole/trimethoprim nor a fluoroquinolone is a preferred option as it may result in hemolysis. Currently, there is a paucity of data regarding treatment of S maltophilia infection in these patients. This case report presents a patient who was successfully treated with doxycycline and inhaled colistimethate.

Acinetobacter baumannii is an important cause of postneurosurgical meningitis. The emergence of carbapenem-resistant strains in this setting has caused a therapeutic challenge. We investigated the clinical implications of postneurosurgical meningitis caused by carbapenem-resistant A. baumannii. In this study, we retrospectively reviewed the medical records of patients more than 16 years of age with A. baumannii meningitis that developed after a neurosurgical procedure at five university-affiliated hospitals between January 2005 and May 2011. Of 40 cases identified, 22 (55.0 %) were caused by carbapenem-resistant strains. Of those evaluable 36 patients with A. baumannii meningitis, 14 (38.9 %) died of meningitis. Meningitis-related mortality was significantly related to carbapenem resistance (59.1 % versus 7.1 %; P = 0.002). In patients with meningitis caused by carbapenem-resistant A. baumannii, colistimethate-containing regimens (4/13 versus 7/9; P = 0.040), intrathecal or intraventricular (IT/IVR) administration of antibiotics (2/13 versus 8/9; P = 0.001), and combined intravenous and IT/IVR therapy (2/13 versus 6/9; P = 0.026) were significantly associated with cure. This study shows that use of colistimethate and combined systemic and local administration of antibiotics should be considered for the treatment of meningitis caused by carbapenem-resistant A. baumannii.

Background: patients prefer dry powder inhalation to nebulisation but the Colobreathe dry powder inhaler for colistimethate sodium (CMS) is not well appreciated in the Netherlands for a number of different reasons, including serious cough problems by some patients after inhalation of the drug. Aim: to assess the suitability of the Twincer as alternative to the Colobreathe for patients having problems with this capsule based inhaler. Methods: in vitro evaluation of the Twincer (55 mg) and Colobreathe (125 mg) was performed using the Next Generation Impactor and a laser diffraction apparatus (Sympatec HELOS) operated at 4 kPa (inhalation volume: 4L; n = 3). Results: laser diffraction analyses shows a finer aerosol from the Twincer than from the Colobreathe. Delivered CMS doses and fine particle doses (FPFs 1-5 µm) from Colobreathe were 126 mg (+14.7/-31.9 mg) and 25.5 mg (+2.8/-3.5 mg) respectively versus 48.5 mg (+2.9/-3.3 mg) and 26.4 mg (+1.4/-1.2 mg) from Twincer. Capsule fragmentation and emission of capsule fragments was observed during evaluation of the Colobreathe but not for the Twincer (having the drug in an aluminum blister). Conclusions: The higher dispersion efficiency of the Twincer (FPF is 54.4% of delivered dose versus 20.2% for Colobreathe) enables to inhale a much lower dose (at lower flow rate) without capsule fragments in the aerosol. As a consequence, the Twincer is expected to be better tolerated by patients and, therefore, provides a suitable alternative to the Colobreathe. This expectation is corroborated by positive feedback from the first patients suffering from CF or non-CF bronchiectasis who received the Twincer on the basis of 9medical need9.

In this issue of Clinical Infectious Diseases, Nation and colleagues (from a consortium of academic institutions in Australia, the United States, Thailand, and Greece) present a critical analysis of the United States (Food and Drug Administration [FDA]) and European (European Medicines Agency [EMA]) dosing recommendations for the intravenous administration of colistin in relation with pharmacokinetic/pharmacodynamic target attainment rates [1]. Together with the large number of recent publications from members of this consortium and other academic institutions, this analysis and the efforts of both regulatory agencies come at an appropriate time and also illustrate a new paradigm in drug development. Colistin is indeed a quite old antibiotic (isolated in Japan in 1949 from Bacillus polymyxa var colistinus). It was only sparingly used in human clinical practice for parenteral administration until the emergence of multi- and panresistant gram-negative organisms in the beginning of this century [2]—that is, at a time when it was no longer under patent protection. In parallel, colistin has been and is still used in large amounts in animals both for curative treatments and for prevention of disease [3]. As a result, there was no or little interest for the pharmaceutical industry to meet the expectations of clinicians when requesting information and hard data about optimal human dosages. Likewise, no effort was made at re-registering colistin for treatment of infections caused by resistant organisms. This may be understandable in a context of drug development made essentially by profit-making industries, which has been and is still largely the system in which most industrial countries have been able to obtain modern medicines. There was also a fear from industry that regulatory agencies would never approve colistin for the indications required by clinicians given the many uncertainties about its true pharmacokinetics (complicated by the fact that colistin is used in humans as prodrug [colistimethate], which hydrolyzes to liberate active colistin rather slowly), its ability to control infections alone (thus requiring combination therapies), and the potential for nephro- and neurotoxic reactions. Thus, colistin may be unique so far in having known a development for human

Colistin (polymyxin E) is a mainly concentration-dependent bactericidal antimicrobial active against multidrug-resistant Gram-negative bacteria. After being abandoned over the past 30 years due to its neuro- and nephrotoxicity, colistin has been reintroduced recently as a last-resort drug for the treatment of multidrug-resistant Gram-negative bacteria infections in combination with other antimicrobials. Unfortunately, although renal toxicity is a well-known dose-related adverse effect of colistin, relatively few studies are currently available on its peculiar pharmacodynamic/pharmacokinetic properties in clinical settings at high risk for drug accumulation, such as acute or chronic kidney disease. In these specific contexts, the risk for underdosing is also substantial because colistin can be easily removed by dialysis/hemofiltration, especially when the most efficient modalities of renal replacement therapy (RRT) are used in critically ill patients. For this reason, recent recommendations in patients undergoing RRT have shifted toward higher dosing regimens, and therapeutic drug monitoring is advised. This review aims to summarize the main issues related to chemical structure, pharmacodynamics/pharmacokinetics, and renal toxicity of colistin. Moreover, recent data and current recommendations concerning colistin dosing in patients with reduced kidney function, with special regard to those receiving RRT such as dialysis or hemofiltration, are also discussed.

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Colistin (polymyxin E), an old antibiotic replaced by other less toxic antibiotics in the 1970s, has been increasingly used over the last decade due to multidrug-resistance in Gram-negative bacteria and lack of new antibiotics. However, there is a dearth of information on the pharmacokinetics (PK), pharmacodynamics (PD) and toxicodynamics (TD) of colistin and its non-active prodrug colistimethate sodium (CMS). Optimised dose regimens have not been established for different types of patients. Additionally, most PK data available in the literature were obtained from concentrations derived from potentially misleading microbiological assays. Therefore, it is urgent to conduct prospective studies to optimise CMS/colistin use in patients, in particular the critically ill. This review summarises recent key clinical studies evaluating the efficacy, toxicity and PK/PD of colistin/CMS.

Multidrug-resistant pathogens are becoming more difficult to treat with significantly increasing infection rates. The lack of new antibiotics to combat these strains has led to the resurgence of older antibiotics. This case highlights the first reported use of colistimethate sodium treatment in a 23-week gestational-age neonate with multidrug-resistant Acinetobacter baumannii pneumonia who developed acute renal failure and seizures shortly after initiation of treatment.

Emergence of multidrug-resistant Gram-negative nosocomial pathogens has led to resurgence of colistin use. Safety and efficacy data regarding colistin use in pediatric patients are sparse, while optimal dosage has not been defined. We present a case series of neonates and children without cystic fibrosis treated with various doses of colistin intravenously. The records of patients who received colistin in a tertiary-care hospital from January 2007 to March 2009 were reviewed. Thirteen patients (median age 5 years, range 22 days to 14 years) received 19 courses of colistin as treatment of pneumonia, central nervous system infection, bacteremia, or complicated soft tissue infection. The isolated pathogens were Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Daily dose of colistin (colistimethate) ranged between 40,000 and 225,000 IU/kg. Duration of administration ranged from 1 to 133 days. Other antimicrobials were co-administered in 18/19 courses. Increase of serum creatinine in one patient was associated with co-administration of colistin and gentamicin. Sixteen of 19 courses had a favorable outcome, and only two of the three deaths were infection-related. Colistin intravenous administration appears well tolerated even at higher than previously recommended doses and of prolonged duration.

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

The increasing frequency of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has led to the reappraisal of colistimethate use.We present a case series of critically ill pediatric patients without cystic fibrosis who received intravenous colistimethate treatment. All available relevant medical records were reviewed.Seven children without cystic fibrosis (mean age 7.7 years; 2 female), admitted to the intensive care unit of a tertiary-care pediatric hospital in Athens, Greece, were identified to have received intravenous colistimethate during October 2004 to May 2008. MDR Acinetobacter baumannii, Pseudomonas aeruginosa, and/or Klebsiella pneumoniae were isolated from blood and/or bronchial secretions specimens in 6 of 7 reported patients. All isolates were susceptible to colistin. All 7 patients received intravenous colistimethate in a dosage of 5 mg/kg daily (divided in 3 equal doses, administered every 8 hours). Five children received colistimethate for 10 days and the remaining 2 for 2 and 23 days, respectively. The infections caused by MDR Gram-negative bacteria were improved in 6 children with microbiologically documented infections. Five of the 7 children were discharged from the ICU. The remaining 2 children died (1 of them had received colistimethate for 2 days); their death was not attributed to MDR Gram-negative infection. No nephrotoxicity or other type of toxicity of colistimethate was noted in this case-series.Although the small number of included cases precludes any firm conclusions, our study suggests that colistimethate may have a role for the treatment of infections caused by MDR Gram-negative bacteria in critically ill pediatric patients.

Resume L’usage de la colistine s’est repandu au cours des dernieres annees avec l’apparition de bacteries a Gram negatif multiresistantes. En reanimation, cet antibiotique initialement abandonne en raison d’une toxicite supposee, revient en premiere ligne pour le traitement des infections a Acinetobacter baumannii et Pseudomonas aeruginosa multiresistants. Dans cette situation, la colistine est le plus souvent utilisee par voie intraveineuse et en association. Malheureusement, la pauvrete des etudes pharmacocinetiques et pharmacodynamiques bien conduites actuellement disponibles ne permet pas d’optimiser son administration afin d’obtenir une efficacite maximale et diminuer le risque d’effets indesirables.

BACKGROUND: Colistin is uncommonly used in clinical practice; however, the emergence of multidrug-resistant organisms has rekindled interest in this potentially toxic therapeutic option. The present study describes the authors’ experience with colistin in the management of patients who were infected with metallo-beta-lactamase (MBL)-producingPseudomonas aeruginosawithin the Calgary Health Region (Calgary, Alberta).METHOD: Adult patients who received colistimethate sodium (colistin) between January 2000 and December 2005 were identified via pharmacy records, and their charts were reviewed retrospectively. Patients with cystic fibrosis were excluded. Patient demographics, clinical course and relevant laboratory data were extracted.RESULTS: Twenty-eight courses of colistin were received by 22 patients. The majority of these treatments were directed at MBL-producingPseudomonas. One-half of the patients received nebulized colistin. Intravenous (IV) colistin was administered to 12 patients for a mean ± SD of 14.7±13.8 days (range 3.7 to 46 days). The highest IV dose used was 125 mg every 6 h or 6 mg/kg/day. Eight of 12 patients (67%) treated with IV colistin responded either fully or partially. Two patients received IV colistin as outpatients. Adverse effects considered to be due to colistin included drug fever, nephrotoxicity and neurotoxicity. Five of nine patients (56%) who had complete data available for evaluation had at least a doubling of creatinine levels from baseline.CONCLUSION: Patients in the present study received both IV and nebulized colistin for multidrug-resistantP aeruginosa. The use of IV colistin was associated with a favourable response, but mild nephrotoxicity occurred in two-third of patients. It was concluded that colistin may be a useful drug when choices are limited.

BACKGROUND: Cystic fibrosis (CF) affects the respiratory and digestive systems. It evolves toward deterioration of pulmonary function through colonization withPseudomonas aeruginosa. There is no consensus with respect to its eradication. Nebulized colistimethate is used for eradication treatment, but the optimal dose and duration is yet to be determined.OBJECTIVES: To compare the efficacy of two doses of nebulized colistimethate (30 mg versus 75 mg twice daily) for the eradication ofP aeruginosain children with CF and intermittent colonization.METHODS: A cohort study with both historical (30 mg) and prospective (75 mg) arms was conducted from 1999 to 2003. Medical records were used to collect data.RESULTS: Eighty-one patients were recruited in the retrospective group, for a total of 111 treatment courses. Twenty patients were recruited in the prospective group, for a total of 20 events. There was no statistically significant difference in the rate of eradication ofP aeruginosaat days 28 and 90, neither when comparing the doses of colistimethate nor duration of treatment. There was a statistically significant difference (P=0.004) between days 1 and 90 in all analyzed subgroups (regardless of dose or duration of treatment) for forced vital capacity only. In the group of patients in whom eradication was achieved at day 28 (after receiving a three-week treatment course of colistimethate), 50% of patients developed a new infection 5.75 months later, on average, regardless of the dose administered. In the group of patients who achieved eradication at day 90 (after receiving a 15-week treatment course of colistimethate), 50% of the 14 patients developed a new infection after an average period of 7.3 months (P=0.28).CONCLUSIONS: There is no difference in the efficacy between a 30 mg dose and a 75 mg dose of colistimethate forP aeruginosaeradication in children with CF and intermittent colonization.

Purpose of review Treatment options for individuals with cystic fibrosis (CF) have improved survival significantly over the past two decades. One important treatment modality is inhaled antibiotics to treat chronic infection of the airways. This review includes those antibiotics that are currently in use, those that are in clinical trials. It also includes review of nonantibiotic antimicrobials, a growing area of investigation in CF. Recent findings There are currently three inhaled antibiotics that are approved for use in patients with cystic fibrosis: tobramycin, aztreonam, and colistimethate. Tobramycin and colistimethate now are available as solution and new dry powder formulations, which are helping the treatment burden which has increased in CF. New antibiotics are in trial, although recently two did not meet primary outcomes in large clinical trials. Of particular interest is the development of nonantibiotic antimicrobials, which may allow treatment of intrinsically antibiotic resistant organisms. Summary Inhaled antibiotics remain an important treatment option in cystic fibrosis due to chronic airway infection as a hallmark of the disease. Although there are now multiple options for treatment, improvements in this treatment class are needed to treat intrinsically resistant organisms. New formulation of antibiotics and nonantibiotic antimicrobials are being evaluated to add to our armamentarium.

Introduction: The lack of adherence is involved in treatment failure. The aim of the study is to assess adherence and clinical and bacteriological effectiveness of nebulized treatment with sodium colistimethate (Promixin®) inhaled by I-neb® device in patients with non-cystic fibrosis bronchiectasis colonized by Pseudomonas aeruginosa (PsA). Patients and Methods: A prospective, multicenter, observational, longitudinal study of a cohort of adults treated for at least 6 months with Promixin®. Compliance data were collected with the computer platform Insight. Lung function data, sputum bacteriology and number of exacerbations and hospital admission in the previous year and after treatment were analysed. Results: 106 patients, 57 males (53.8%), average age 64.0 ± 14.6 years. The post-infectious aetiology was the most frequent and PsA was the only isolated pathogen in 84% of cases. The mean treatment time was 26.8 ± 16.7 months (6.1 to 63.9). Proper nebulizer management was 96.6 ± 7.8% and real adherence 84.3±20.2%. Relevant clinical data are collected in the. Conclusions: In our cohort, nebulizer management and real adherence to treatment with Promixin® were excellent with an improvement in lung function, number of exacerbations and need for admission to hospital.

The purpose of this study was to evaluate the pulmonary and systemic pharmacokinetics of colistin following a single dose of nebulized colistimethate sodium (CMS) in mechanically ventilated neonates. We administered a single dose of nebulized CMS (approximately 120,000 IU/kg of CMS, equivalent to 4 mg/kg colistin base activity) to 6 ventilated neonates with ventilator-associated pneumonia. The median gestational age was 39 weeks (range, 32-39 weeks). Mean (± SD) tracheal aspirate colistin maximum concentration (Cmax), area under the concentration-time curve (AUC 0-24) and t1/2 were 24.0 ± 8.2 μg/mL, 147.6 ± 53.5 μg · hours/mL and 9.8 ± 5.5 hours, respectively. The plasma concentrations of colistin were low. In neonates, a single nebulized dose of CMS (120,000 IU) resulted in high local concentrations for at least 12 hours and low systemic concentrations of colistin. Twice daily nebulization might be more appropriate.

Colistin has been revived, in the era of extensively drug-resistant (XDR) Gram-negative infections, as the last-resort treatment in critically ill patients. Recent studies focusing on the optimal dosing strategy of colistin have demonstrated the necessity of a loading dose at treatment initiation (D. Plachouras, M. Karvanen, L. E. Friberg, E. Papadomichelakis, A. Antoniadou, I. Tsangaris, I. Karaiskos, G. Poulakou, F. Kontopidou, A. Armaganidis, O. Cars, and H. Giamarellou, Antimicrob Agents Chemother 53:3430–3436, 2009, http://dx.doi.org/10.1128/AAC.01361-08 ; A. F. Mohamed, I. Karaiskos, D. Plachouras, M. Karvanen, K. Pontikis, B. Jansson, E. Papadomichelakis, A. Antoniadou, H. Giamarellou, A. Armaganidis, O. Cars, and L. E. Friberg, Antimicrob Agents Chemother 56:4241– 4249, 2012, http://dx.doi.org/10.1128/AAC.06426-11 ; S. M. Garonzik, J. Li, V. Thamlikitkul, D. L. Paterson, S. Shoham, J. Jacob, F. P. Silveira, A. Forrest, and R. L. Nation, Antimicrob Agents Chemother 55:3284–3294, 2011, http://dx.doi.org/10.1128/AAC.01733-10 ). In 19 critically ill patients with suspected or microbiologically documented infections caused by XDR Gram-negative strains, a loading dose of 9 MU colistin methanesulfonate (CMS) (∼270 mg colistin base activity) was administered with a maintenance dose of 4.5 MU every 12 h, commenced after 24 h. Patients on renal replacement were excluded. CMS infusion was given over 30 min or 1 h. Repeated blood sampling was performed after the loading dose and after the 5th or 6th dose. Colistin concentrations and measured CMS, determined after hydrolization to colistin and including the partially sulfomethylated derivatives, were determined with a liquid chromatography-tandem mass spectrometry assay. Population pharmacokinetic analysis was conducted in NONMEM with the new data combined with data from previous studies. Measured colistimethate concentrations were described by 4 compartments for distribution and removal of sulfomethyl groups, while colistin disposition followed a 1-compartment model. The average observed maximum colistin A plus B concentration was 2.65 mg/liter after the loading dose (maximum time was 8 h). A significantly higher availability of the measured A and B forms of colistimethate and colistin explained the higher-than-expected concentrations in the present study compared to those in previous studies. Creatinine clearance was a time-varying covariate of colistimethate clearance. The incidence of acute renal injury was 20%.