Colistin utilization at a tertiary hospital in South Africa: an opportunity for antimicrobial stewardship practices.

Introduction. Colistin (polymyxin E) has emerged as a last-resort treatment option for multidrug-resistant infections.Hypothesis/Gap Statement. Studies on the use, safety and efficacy of colistin in South Africa are limited.Aim. This study aims to describe the use of colistin and its clinical outcomes at a tertiary public hospital in South Africa.Methodology. We conducted a retrospective review of adult and paediatric patients who received parenteral colistin between 2015 and 2019.Results. A total of 69 patients (26 adults, 13 children and 30 neonates) were reviewed. Acinetobacter baumannii was the most common causative pathogen isolated (70.1 %). Colistin was predominately used to treat septicaemia (75.4 %). It was primarily administered as definitive therapy (71.0 %) and as monotherapy (56.5 %). It was used in 11.5 % of adults with infections susceptible to other antibiotics. Loading doses of intravenous colistin were administered in only 15 (57.7 %) adult patients. Neurotoxicity and nephrotoxicity occurred in 5.8 % and 43.5 % of patients, respectively. Clinical cure was achieved in 37 (53.6 %) patients. On multivariate logistic regression analysis, adults [adjusted odds ratio (aOR), 25.54; 95 % CI, 2.73-238.65; P < 0.01] and children (aOR, 8.56; 95 % CI, 1.06-69.10; P < 0.05) had higher odds of death than neonates.Conclusion. The study identified significant stewardship opportunities to improve colistin prescription and administration. Achieving optimal patient outcomes necessitates a multidisciplinary approach and vigilant monitoring of colistin use.

Using host-mimicking conditions and a murine cutaneous abscess model to identify synergistic antibiotic combinations effective against Pseudomonas aeruginosa.

Antibiotic drug combination therapy is critical for the successful treatment of infections caused by multidrug resistant pathogens. We investigated the efficacy of ß-lactam and ß-lactam/ß-lactamase inhibitor combinations with other antibiotics, against the hypervirulent, ceftazidime/avibactam resistant Pseudomonas aeruginosa Liverpool epidemic strain (LES) B58. Although minimum inhibitory concentrations in vitro differed by up to eighty-fold between standard and host-mimicking media, combinatorial effects only marginally changed between conditions for some combinations. Effective combinations in vitro were further tested in a chronic, high-density murine infection model. Colistin and azithromycin demonstrated combinatorial effects with ceftazidime and ceftazidime/avibactam both in vitro and in vivo. Conversely, while tobramycin and tigecycline exhibited strong synergy in vitro, this effect was not observed in vivo. Our approach of using host-mimicking conditions and a sophisticated animal model to evaluate drug synergy against bacterial pathogens represents a promising approach. This methodology may offer insights into the prediction of combination therapy outcomes and the identification of potential treatment failures.

Efficacy of adjunctive inhaled colistin and tobramycin for ventilator-associated pneumonia: systematic review and meta-analysis.

INTRODUCTION: Ventilator-associated pneumonia (VAP) presents a significant challenge in intensive care units (ICUs). Nebulized antibiotics, particularly colistin and tobramycin, are commonly prescribed for VAP patients. However, the appropriateness of using inhaled antibiotics for VAP remains a subject of debate among experts. This study aims to provide updated insights on the efficacy of adjunctive inhaled colistin and tobramycin through a comprehensive systematic review and meta-analysis. METHODS: A thorough search was conducted in MEDLINE, EMBASE, LILACS, COCHRANE Central, and clinical trials databases ( www. CLINICALTRIALS: gov ) from inception to June 2023. Randomized controlled trials (RCTs) meeting specific inclusion criteria were selected for analysis. These criteria included mechanically ventilated patients diagnosed with VAP, intervention with inhaled Colistin and Tobramycin compared to intravenous antibiotics, and reported outcomes such as clinical cure, microbiological eradication, mortality, or adverse events. RESULTS: The initial search yielded 106 records, from which only seven RCTs fulfilled the predefined inclusion criteria. The meta-analysis revealed a higher likelihood of achieving both clinical and microbiological cure in the groups receiving tobramycin or colistin compared to the control group. The relative risk (RR) for clinical cure was 1.23 (95% CI: 1.04, 1.45), and for microbiological cure, it was 1.64 (95% CI: 1.31, 2.06). However, there were no significant differences in mortality or the probability of adverse events between the groups. CONCLUSION: Adjunctive inhaled tobramycin or colistin may have a positive impact on the clinical and microbiological cure rates of VAP. However, the overall quality of evidence is low, indicating a high level of uncertainty. These findings underscore the need for further rigorous and well-designed studies to enhance the quality of evidence and provide more robust guidance for clinical decision-making in the management of VAP.

Dry powder inhalation containing muco-inert ciprofloxacin and colistin co-loaded liposomes for pulmonary P. Aeruginosa biofilm eradication.

Pseudomonas aeruginosa (PA), a predominant pathogen in lung infections, poses significant challenges due to its biofilm formation, which is the primary cause of chronic and recalcitrant pulmonary infections. Bacteria within these biofilms exhibit heightened resistance to antibiotics compared to their planktonic counterparts, and their secreted toxins exacerbate lung infections. Diverging from traditional antibacterial therapy for biofilm eradication, this study introduces a novel dry powder inhalation containing muco-inert ciprofloxacin and colistin co-encapsulated liposomes (Cipro-Col-Lips) prepared using ultrasonic spray freeze drying (USFD) technique. This USFD dry powder is designed to efficiently deliver muco-inert Cipro-Col-Lips to the lungs. Once deposited, the liposomes rapidly diffuse into the airway mucus, reaching the biofilm sites. The muco-inert Cipro-Col-Lips neutralize the biofilm-secreted toxins and simultaneously trigger the release of their therapeutic payload, exerting a synergistic antibiofilm effect. Our results demonstrated that the optimal USFD liposomal dry powder formulation exhibited satisfactory in vitro aerosol performance in terms of fine particle fraction (FPF) of 44.44 ± 0.78 %, mass median aerodynamic diameter (MMAD) of 4.27 ± 0.21 µm, and emitted dose (ED) of 99.31 ± 3.31 %. The muco-inert Cipro-Col-Lips effectively penetrate the airway mucus and accumulate at the biofilm site, neutralizing toxins and safeguarding lung cells. The triggered release of ciprofloxacin and colistin works synergistically to reduce the biofilm's antibiotic resistance, impede the development of antibiotic resistance, and eliminate 99.99 % of biofilm-embedded bacteria, including persister bacteria. Using a PA-beads induced biofilm-associated lung infection mouse model, the in vivo efficacy of this liposomal dry powder aerosol was tested, and the results demonstrated that this liposomal dry powder aerosol achieved a 99.7 % reduction in bacterial colonization, and significantly mitigated inflammation and pulmonary fibrosis. The USFD dry powder inhalation containing muco-inert Cipro-Col-Lips emerges as a promising therapeutic strategy for treating PA biofilm-associated lung infections.

Intravenous fosfomycin for treatment of severe infections caused by carbapenem-resistant Acinetobacter baumannii: A multi-centre clinical experience.

BACKGROUND: Severe infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) have been reported increasingly over the past few years. Many in-vivo and in-vitro studies have suggested a possible role of intravenous fosfomycin for the treatment of CRAB infections. METHODS: This multi-centre, retrospective study included patients treated with intravenous fosfomycin for severe infections caused by CRAB admitted consecutively to four hospitals in Italy from December 2017 to December 2022. The primary goal of the study was to evaluate the risk factors associated with 30-day mortality in the study population. A propensity score matched analysis was added to the model. RESULTS: One hundred and two patients with severe infections caused by CRAB treated with an intravenous fosfomycin-containing regimen were enrolled in this study. Ventilator-associated pneumonia (VAP) was diagnosed in 59% of patients, primary bacteraemia in 22% of patients, and central-venous-catheter-related infection in 16% of patients. All patients were treated with a regimen containing intravenous fosfomycin, mainly in combination with cefiderocol (n=54), colistin (n=48) or ampicillin/sulbactam (n=18). Forty-eight (47%) patients died within 30 days. Fifty-eight (57%) patients experienced clinical therapeutic failure. Cox regression analysis showed that diabetes, primary bacteraemia and a colistin-containing regimen were independently associated with 30-day mortality, whereas adequate source control of infection, early 24-h active in-vitro therapy, and a cefiderocol-containing regimen were associated with survival. A colistin-based regimen, A. baumannii colonization and primary bacteraemia were independently associated with clinical failure. Conversely, adequate source control of infection, a cefiderocol-containing regimen, and early 24-h active in-vitro therapy were associated with clinical success. CONCLUSIONS: Different antibiotic regimens containing fosfomycin in combination can be used for treatment of severe infections caused by CRAB.

Inhaled antimicrobial prescribing for Pseudomonas aeruginosa infections in Europe.

BACKGROUND: Prescribers have an increasing range of inhaled antimicrobial formulations to choose from when prescribing both eradication and chronic suppression regimens in cystic fibrosis (CF). This study aimed to investigate the decision-making process behind prescribing of inhaled antimicrobials for Pseudomonas aeruginosa infections. METHODS: A questionnaire was developed using Microsoft Forms and then forwarded to 57 Principal Investigators (PIs), at each of the CF centres within the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN). Data collection occurred between November 2021 and February 2022. RESULTS: The response rate was 90 % (n = 51/57 PIs), with at least 50 % of CF centers in each of the 17 countries represented in the ECFS-CTN. Physicians used a median of eight factors in their decision-making process with delivery formulations (92.2 %), adherence history (84.3 %), and antibiotic side-effect profile (76.5 %) often selected. Nebulised tobramycin or colistin were frequently selected as the inhaled antimicrobial in first-line eradication (n = 45, 88.2 %) and chronic suppression regimens (n = 42, 82.4 %). Combination regimens were more often chosen in eradication (first-line: n = 35, 68.6 %, second-line: n = 34, 66.7 %) and later chronic suppression regimens (third-line: n = 27, 52.9 %) than monotherapy. For pwCF also prescribed CFTR modulator therapies, most PIs did not alter inhaled antimicrobial regimens (n = 40, 78.4 %), with few pwCF (n = 18, 35.3 %) or PIs (n = 10, 19.6 %) deciding to stop inhaled antimicrobials. CONCLUSIONS: The inhaled antimicrobial prescribing decision-making process is multifactorial. Nebulised tobramycin or colistin are often used in initial eradication and chronic suppression regimens. To date, CFTR modulator therapy has had a limited impact on the prescribing of inhaled antimicrobial regimens.

Physical compatibility of colistin with analgesics during simulated Y-site administration.

PURPOSE: Special consideration is needed when intravenous drugs are administered simultaneously using a Y-site connector. This study aimed to investigate the physical compatibility of colistin with 6 analgesics at concentrations commonly used in clinical practice. METHODS: A pharmaceutical preparation of colistin was dissolved according to the manufacturer's instructions and diluted to a concentration of 1.5 mg/mL or 0.67 mg/mL (of colistin base). Simulated administration via Y-site infusion set was performed by mixing 5 mL of colistin solution with an equal volume of a solution of one of 6 intravenous analgesics. Infusion solutions of ibuprofen, ketoprofen, metamizole sodium, morphine sulfate, paracetamol, and tramadol hydrochloride were studied. For each analgesic tested, concentrates for injection were diluted with 2 solvents, resulting in 11 different combinations with each concentration of the colistin solution. The mixtures were visually inspected, and their turbidity was measured directly after mixing and at 3 consecutive time points (30, 60, and 120 minutes). Additionally, the pH of the mixtures was measured after 120 minutes and compared with the pH of the analgesic and the colistin solutions. RESULTS: During visual inspection with the unaided eye, no precipitate formation or gas evolution was observed in any of the tested analgesics except for sodium metamizole, where the yellow color of the solutions was observed. For samples containing the mixture of ibuprofen and colistin, the turbidity measurements revealed the presence of turbidity in the studied mixtures. The greatest change in pH relative to the value immediately after preparation was noted for combinations of ketoprofen and morphine sulfate with the tested antibiotic. CONCLUSION: Colistin was found to be incompatible with ibuprofen and metamizole sodium formulations. It should also not be combined with morphine sulfate due to the significant differences in the pH value of the preparations. The colistin 0.67 mg/mL and 1.5 mg/mL infusion solutions were physically compatible with ketoprofen, tramadol hydrochloride, and paracetamol.

Phloretin potentiates polymyxin E activity against gram-negative bacteria.

AIMS: The spread of plasmid-mediated polymyxin resistance has jeopardized the use of polymyxin, the last defender that combats infections caused by multidrug-resistant (MDR) gram-negative pathogens. MAIN METHODS: In this study, phloretin, as a monomeric compound extracted from natural plants, showed a good synergistic effect with polymyxin E against gram-negative bacteria, as evaluated by minimal inhibit concentration (MIC) assay and a series of assays, including growth curve, time-killing, and Western blot assays. A model of mice infected by Salmonella sp. stain HYM2 was established to further identify the synergistic effect of phloretin with polymyxin E. KEY FINDINGS: The results suggested that phloretin had the potential ability to recover the antibacterial sensitivity of polymyxin E from 64 µg/mL to no more than 2 µg/mL in E. coli ZJ478 or in Salmonella sp. stain HYM2 with a 32-fold decrease. A series of strains, including mcr-1-positive and mcr-1-negative strains, were treated with a combination of phloretin and polymyxin E, and the fractional inhibitory concentration (FIC) values were all found to be below 0.5. However, the combination of phloretin and polymyxin E did not lead to bacterial resistance. In vivo, the survival rate of infected mice reached nearly 80% with the combination treatment, and the cecal colony value also decreased significantly. SIGNIFICANCE: All the above results indicated that phloretin is a potential polymyxin potentiator to combat gram-negative stains.

Spray-freeze-dried inhalable composite microparticles containing nanoparticles of combinational drugs for potential treatment of lung infections caused by Pseudomonas aeruginosa.

The multi-drug resistance of Pseudomonas aeruginosa is an overwhelming cause of terminal and persistent lung infections in cystic fibrosis (CF) patients. Antimicrobial synergy has been shown for colistin and ivacaftor, and our study designed a relatively high drug-loading dry powder inhaler formulation containing nanoparticles of ivacaftor and colistin. The ivacaftor-colistin nanosuspensions (Iva-Col-NPs) were prepared by the anti-solvent method with different stabilizers. Based on the aggregation data, the formulation 7 (F7) with DSPG-PEG-OMe as the stabilizer was selected for further studies. The F7 consisted of ivacaftor, colistin and DSPG-PEG-OMe with a mass ratio of 1:1:1. The F7 powder formulation was developed using the ultrasonic spray-freeze-drying method and exhibited a rough surface with relatively high fine particle fraction values of 61.4 ± 3.4% for ivacaftor and 63.3 ± 3.3% for colistin, as well as superior emitted dose of 97.8 ± 0.3% for ivacaftor and 97.6 ± 0.5% for colistin. The F7 showed very significant dissolution improvement for poorly water soluble ivacaftor than the physical mixture. Incorporating two drugs in a single microparticle with synchronized dissolution and superior aerosol performance will maximize the synergy and bioactivity of those two drugs. Minimal cytotoxicity in Calu-3 human lung epithelial cells and enhanced antimicrobial activity against colistin-resistant P. aeruginosa suggested that our formulation has potential to improve the treatment of CF patients with lung infections.

Comparison of different colistin regimens for the treatment of pneumonia caused by multidrug-resistant microorganisms: a systematic review and meta-analysis.

OBJECTIVE: Multidrug-resistant pneumonia is a common cause of hospital-related morbidity and mortality across the world. The high prevalence of multidrug-resistant pneumonia due to resistant gram-negative pathogens has led to a re-introduction of colistin. The adverse events associated with intravenous colistin can be alleviated by administering the drug nasally (i.e., inhalation) or in a combination including both inhalation and intravenous presentations of the drug. A review study compared the impact of these administration methods on clinical, morbidity, and mortality-related outcomes in patients with multiple-drug resistant pneumonia. However, the publication of newer cohort trials, warrants an update of the state of the evidence. To compare the clinical, morbidity, and mortality outcomes in patients with multidrug-resistant pneumonia receiving either intravenous colistin or combined drug presentations (ie, inhaled and intravenous). MATERIALS AND METHODS:  A systematic search of the academic literature was performed according to the PRISMA guidelines across five databases (Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE). We conducted a random-effect meta-analysis to compare outcomes such as rate of clinical cure, microbiological eradication, nephrotoxicity, and overall mortality in patients with multidrug-resistant pneumonia receiving either intravenous colistin, inhaled colistin, or a combination of those administration routes. RESULTS:  From 963 studies, we found 16 eligible studies with 1651 patients (61.6 ± 7.7 years) with multidrug-resistant pneumonia who had received either intravenous, inhaled colistin or a combined inhaled/intravenous administration. Our meta-analysis revealed higher rates of clinical cure (OR, 1.61) and microbiological eradication (1.37) in patients receiving combined intravenous/inhaled colistin than in those receiving intravenous colistin alone. Additional analyses revealed higher rates of nephrotoxicity (1.30) and mortality (1.44) in patients receiving intravenous colistin than in those receiving combined intravenous/inhaled colistin. CONCLUSIONS:  We provide evidence showing improved clinical, morbidity, and mortality outcomes in patients with multidrug-resistant pneumonia receiving inhaled colistin or combined inhaled/intravenous colistin than those receiving intravenous colistin alone. These findings should help clinicians stratify the risks associated with different colistin administration routes to manage multidrug-resistant pneumonia.

Efficacy of Problem-Solving Intervention to Improve Adherence in Adolescents and Adults with Cystic Fibrosis.

BACKGROUND: Adherence to treatment by adolescents and adults with cystic fibrosis (CF) is often poor. OBJECTIVES: To assess the impact of a focused clinical intervention on adherence in individual patients, including help in problem-solving key barriers to adherence. To implement a patient-centered problem-solving intervention using CF My Way tools. To identify and overcome a selected barrier to adherence. METHODS: Medication possession ratios (MPRs), number of airway clearance sessions, forced expiratory volume (FEV1), body mass index (BMI), and health-related quality of life (HRQoL) were measured before and after the intervention. RESULTS: Sixteen patients with CF, aged 23.4 ± 6.7 years, participated. MPR increased for colistimethate sodium and tobramycin inhalations from a median of 21 (range 0-100) to 56 (range 0-100), P = 0.04 and 20 (range 0-100) to 33.3 (range 25-100), P = 0.03, respectively. BMI standard deviation score rose from -0.37 to -0.21, P = 0.05. No significant improvements were found in FEV1, airway clearance, or HRQoL scores. CONCLUSIONS: The CF My Way problem-solving intervention increased adherence to medical treatments by removing barriers directly related to the needs and goals of young adults with CF.

Hyaluronan/Diethylaminoethyl Chitosan Polyelectrolyte Complexes as Carriers for Improved Colistin Delivery.

Improving the therapeutic characteristics of antibiotics is an effective strategy for controlling the growth of multidrug-resistant Gram-negative microorganisms. The purpose of this study was to develop a colistin (CT) delivery system based on hyaluronic acid (HA) and the water-soluble cationic chitosan derivative, diethylaminoethyl chitosan (DEAECS). The CT delivery system was a polyelectrolyte complex (PEC) obtained by interpolymeric interactions between the HA polyanion and the DEAECS polycation, with simultaneous inclusion of positively charged CT molecules into the resulting complex. The developed PEC had a hydrodynamic diameter of 210-250 nm and a negative surface charge (ζ-potential = -19 mV); the encapsulation and loading efficiencies were 100 and 16.7%, respectively. The developed CT delivery systems were characterized by modified release (30-40% and 85-90% of CT released in 15 and 60 min, respectively) compared to pure CT (100% CT released in 15 min). In vitro experiments showed that the encapsulation of CT in polysaccharide carriers did not reduce its antimicrobial activity, as the minimum inhibitory concentrations against Pseudomonas aeruginosa of both encapsulated CT and pure CT were 1 µg/mL.

Determination of the retinal toxicity of intravitreal colistin in rabbit eyes.

PURPOSE: To determine the possible adverse effects and safe dose range of intravitreal colistin, an antibiotic, after its intravitreal application. METHODS: Twenty eyes of 20 adult male and female New Zealand white rabbits were selected. Various concentrations of colistin were prepared. In each rabbit, 0.1 mL of colistin solution or saline solution was injected intravitreally into the right eye. Electroretinographic recordings were taken before and 2 weeks after injection. Histopathological examination was made using a light microscope following enucleation and fixation procedures. In histopathologic cross-sections, the differences between drug-injected eyes and control eyes were evaluated. RESULTS: Electroretinographic examination showed a decrease of 30% as a significant value in the a and b wave amplitudes of the rabbits that injected 400 µg/0.1 ml and higher concentrations. Histological examination revealed histiocytic infiltration, histiocytic vacuoles, inflammation, and retinal degeneration in rabbit eyes given 400 µg/0.1 ml, 800 µg/0.1 ml, and 1.6 mg/0.1 ml concentrations of colistin. CONCLUSION: Based on our findings, the safe concentration of colistin is 0.2 mg/0.1 ml. Administration of 0.4 mg/0.1 ml was associated with cataract development, electrophysiological depression, and pathological changes in retinal layers.

Effect of combined colistin and meropenem against meropenem resistant Acinetobacter baumannii and Pseudomonas aeruginosa by checkerboard method: A cross sectional analytical study.

BACKGROUND: Meropenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are the two most common nosocomial pathogens causing ventilator-associated pneumonia. To combat this resistance, different combinations of antibiotics have been evaluated for their efficacy in laboratories as well as in clinical situations. AIM: The aim of the study was to investigate the effect of combined colistin and meropenem against meropenem-resistant isolates of A. baumannii and P. aeruginosa by checkerboard method. MATERIALS AND METHODS: Fifty meropenem-resistant isolates of A. baumannii (n = 25) and P. aeruginosa (n = 25) from endotracheal aspirates were studied. The MIC of colistin and meropenem was found using the microbroth dilution method. The fractional inhibitory concentration was calculated for the combination of antibiotics by checkerboard assay and the antibiotic interactions were assessed. Fisher's exact test was carried out for statistical comparison of categorical variables. RESULTS: A synergistic effect between colistin and meropenem was observed in 18/25 (72%) and 6/25 (24%) isolates of Acinetobacter baumannnii and P. Aeruginosa, respectively, with fractional inhibitory concentration indices of ≤0.5. None of the tested isolates exhibited antagonism. CONCLUSION: Our results showed that combinations of colistin and meropenem are associated with improvement in minimum inhibitory concentration and may be a promising strategy in treating meropenem-resistant A. baumannii respiratory tract infections.

Toxicologic effect and transcriptome analysis for short-term orally dosed enrofloxacin combined with two veterinary antimicrobials on rat liver.

Presently, toxicological assessment of multiple veterinary antimicrobials has not been performed on mammals. In this study, we assessed the short-term toxicity of enrofloxacin (E) combined with colistin (C) and quinocetone (Q). Young male rats were orally dosed drug mixtures and single drugs in 14 consecutive days, each at the dose of 20, 80, and 400 mg/(kg·BW) for environmental toxicologic study. The results showed that at the high dose treatment, the combination of E + C+Q significantly decreased body intake, lymphocytes count on rats; significantly increased the values of Alanine aminotransferase (ALT), Glutamic oxaloacetic transaminase (AST) and, cholinesterase (CHE); it also got the severest histopathological changes, where sinusoidal congestion and a large number of black particles in sinusoids were observed. This means E + C+Q in the high dose groups was able to cause significant damage to the liver. Other combinations or doses did not induce significant liver damage. Transcriptome analysis was then performed on rats in high dose group for further research. For E + C and E + Q, an amount of 375 and 480 differently expressed genes were filtered out, revealing their possible underlying effect on genomes. For E + C+Q, a weighted gene co-expression network analysis was performed and 96 hub genes were identified to reveal the specific effect induced by this combination. This study indicates that joint toxicity should be taken into consideration when involving the risk assessment of these antimicrobials.

Intraventricular treatment of paediatric meningitis due to extensively drug-resistant Gram-negative bacteria: two case reports and review of the literature.

Nosocomial meningitis caused by Gram-negative bacteria is associated with increasingly common neurosurgical procedures in children, with an increase in incidence recently reported. These infections are associated with an increased risk of mortality, prolonged hospitalisation, and increased costs. In this report, we describe two paediatric cases with central nervous system infections caused by extensively drug-resistant Gram-negative bacteria that were successfully treated with intraventricular colistin. To the best of our knowledge, this is the first comprehensive review and discussion of intraventricular antimicrobial therapy in a paediatric population. Based on our comprehensive review of the relevant literature, it appears that intraventricular administration of colistin may be a promising and effective option in the treatment of central nervous system infections in children who do not respond to other treatment options.

Prevention of colistin induced nephrotoxicity: a review of preclinical and clinical data.

Introduction: The emergence of antimicrobial resistance in Gram-negative bacteria is a concerning challenge for health systems. The polymyxins, including colistin, are one of the limited available options these pathogens management. Nephrotoxicity, beside neurotoxicity is the major dose-limiting adverse reaction of polymyxins, with an up to 60% prevalence. As oxidative stress, inflammatory pathways and apoptosis are considered as the main mechanisms of colistin-induced kidney damage, various studies have evaluated antioxidant and/or antiapoptotic compounds for its prevention. In this article, we reviewed animal and human studies on these probable preventive measures.Area covered: PubMed, Scopus, and google scholar databases were searched using several combination of 'colistin', 'polymyxin E', 'CMS', 'Colistimethate sodium', 'nephrotoxicity', 'kidney injury', 'kidney damage', 'renal injury', 'renal damage', 'nephroprotectants', 'renoprotective', 'nephroprotective', and 'prevention'. All eligible articles including animal and human studies up to the end of 2020 were included.Expert opinion: Most of available studies are in vivo researches on anti-oxidant and anti-apoptotic agents like NAC, vitamin C and E, silymarin, and curcumin which mostly showed promising findings. However, limited human studies on NAC and vitamin C did not demonstrate considerable efficacy. So, before proposing these compounds, further well-designed randomized clinical trials are necessary.

A Novel Validated Injectable Colistimethate Sodium Analysis Combining Advanced Chemometrics and Design of Experiments.

Colistimethate sodium (CMS) is widely administrated for the treatment of life-threatening infections caused by multidrug-resistant Gram-negative bacteria. Until now, the quality control of CMS formulations has been based on microbiological assays. Herein, an ultra-high-performance liquid chromatography coupled to ultraviolet detector methodology was developed for the quantitation of CMS in injectable formulations. The design of experiments was performed for the optimization of the chromatographic parameters. The chromatographic separation was achieved using a Waters Acquity BEH C8 column employing gradient elution with a mobile phase consisting of (A) 0.001 M aq. ammonium formate and (B) methanol/acetonitrile 79/21 (v/v). CMS compounds were detected at 214 nm. In all, 23 univariate linear-regression models were constructed to measure CMS compounds separately, and one partial least-square regression (PLSr) model constructed to assess the total CMS amount in formulations. The method was validated over the range 100-220 µg mL-1. The developed methodology was employed to analyze several batches of CMS injectable formulations that were also compared against a reference batch employing a Principal Component Analysis, similarity and distance measures, heatmaps and the structural similarity index. The methodology was based on freely available software in order to be readily available for the pharmaceutical industry.

Predictors of Acute Kidney Injury and 28-Day Mortality in Carbapenem-Resistant Acinetobacter baumannii Complex Bacteremia.

Colistin is an, antibiotic used to treat carbapenem-resistant Acinetobacter baumannii complex (CRABC) infection. However, colistin is well known for its nephrotoxicity. To accurately assess the effects of colistin on acute kidney injury (AKI) and 28-day mortality, we investigated the risk factors associated with AKI and mortality in patients with CRABC bacteremia who received or never received colistin. Patients with CRABC bacteremia aged ≥18 years were retrospectively identified for 3 years at five tertiary teaching hospitals. AKI was defined by using the Kidney Disease Improving Global Outcomes criteria. AKI developed in 103 (34.9%) of the 295 patients enrolled patients. AKI developed more frequently in patients who received colistin than in patients who did not (46.7% vs. 29.5%, p = 0.004). Multivariate analysis showed that intravenous colistin usage was an independent risk factor for AKI in these patients. Nonfatal disease, catheter-related bloodstream infection, and administration of colistin were protective factors for 28-day mortality. However, the sequential organ failure assessment score and AKI were associated with poor outcomes. In conclusion, colistin may be a double-edged sword; although it causes AKI, it also reduces 28-day mortality in patients with CRABC bacteremia. Therefore, colistin administration as an appropriate antibiotic may improve CRABC bacteremia prognosis, despite its nephrotoxicity.

No increased acute kidney injury rate through giving an intravenous colistin loading dose in pediatric patients.

OBJECTIVES: A colistin loading dose is required to achieve adequate drug exposure for the treatment of multidrug-resistant Gram-negative bacteria. However, data on acute kidney injury (AKI) rates associated with this approach in children have been unavailable. The aim of this study was to examine AKI rates in children who were prescribed a colistin loading dose. METHODS: A retrospective study was conducted in patients aged 1 month to 18 years who had received intravenous colistin for ≥48 h. Loading dose (LD) was defined as colistin methanesulfonate at 4-5 mg of colistin base activity/kg/dose. AKI was defined according to KDIGO serum creatinine (SCr) criteria - SCr ≥ 1.5 times the baseline, measured 3-7 days after colistin initiation. Augmented renal clearance (ARC) was defined as an estimated glomerular filtration rate (eGFR) >150 mL/min/1.73 m2. The rates of AKI were compared between children receiving or not receiving an LD, and between different eGFR groups. RESULTS: In total, 181 children were enrolled. The mean age was 4.3 years (95% confidence interval [CI], 3.6-4.9 years). Ninety-five of the subjects (52.5%) were male. There were 157 children with a baseline eGFR of ≥ 80 mL/min/1.73 m2. The overall AKI rate within the first week in this group was 20.4% (95% CI, 14.4-27.6%): LD, 16.1% vs no LD, 23.2% (p = 0.29). Subgroup analysis, excluding patients with ARC, showed a lower AKI rate of 12.8% (95% CI, 6.8-21.3%): LD, 9.7% vs no LD, 14.3% (p = 0.53). CONCLUSIONS: AKI rate was not different among children who received an intravenous colistin loading dose. This approach should be implemented to ensure the necessary drug exposure required for good treatment outcomes.