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.

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity? / ¿Puede la profilaxis con sulfato de magnesio reducir la nefrotoxicidad de la colistina?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin. (AU)

El objetivo del estudio fue investigar la función de la profilaxis con sulfato de magnesio en la nefrotoxicidad causada por la colistina. Se dividieron 30 ratas Wistar albinas en 4 grupos: control, colistina, magnesio (Mg) y Mg + colistina. Los fármacos se administraron a los grupos durante 7 días. Los valores de urea-creatinina se midieron al principio (T0) y al final (T1) del estudio. Se midieron los niveles de malondialdehído (MDA) en el plasma y el tejido renal, y se analizaron los niveles de glutatión (GSH) en los eritrocitos y el tejido renal. Al final del estudio, se calculó la puntuación semicuantitativa (semiquantitative score [SQS]) mediante el examen histopatológico de los riñones. Los valores de urea disminuyeron significativamente en los grupos de Mg y Mg + colistina en comparación con los valores iniciales (p = 0,013 y p = 0,001). En el momento del T1, estos grupos tenían valores de urea significativamente más bajos que los grupos de colistina y de control. El valor de creatinina se incrementó significativamente en el grupo de colistina en comparación con el valor inicial (p = 0,005); el valor de creatinina en el grupo de colistina fue significativamente mayor que en el grupo de Mg + colistina (p = 0,011). Los niveles de MDA en el plasma fueron significativamente más altos en el grupo de colistina en comparación con los otros grupos en el momento del T1 (p < 0,001). El grupo de Mg + colistina presentó niveles renales de MDA más bajos que el grupo de colistina. El grupo de colistina presentó un grado tubular renal (p = 0,035), un área renal afectada (p < 0,001) y una SQS (p = 0,001) significativamente mayores que el grupo de Mg + colistina. Los resultados del estudio indicaron que el sulfato de Mg puede tener un efecto reductor de la nefrotoxicidad de la colistina. (AU)

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.

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.

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.

Comparisons of adverse event reporting for colistin versus polymyxin B using the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Background: The polymyxins (colistin and polymyxin B) have recently reemerged in clinical practice. With the same antimicrobial activities, colistin has been more frequently prescribed in most countries, although available evidence on their nephrotoxicity is conflicting.Methods: The US Food and Drug Administration Adverse Event Reporting System (FAERS) data from Q1-2004 to Q1-2020 were used to identify adverse events (AE) reports. We described the reporting patterns and compare the reporting rates of serious AEs, acute kidney diseases (AKD), and death between colistin and polymyxin B using reporting odds ratios (RORs).Results: The annual number of AE reports increased over time for both drugs. Heterogeneity in reporting characteristics was observed in age and reporter region. RORs of serious, AKD, and death AEs were significantly higher for both drugs versus other drugs. RORs of serious and AKD AEs were higher for colistin compared to polymyxin B (p = 0.0479 and p = 0.0306, respectively), but no difference in death RORs was detected (p = 0.2211).Conclusions: This study showed higher reporting rates of serious AEs and AKD for colistin than polymyxin B, but no difference in death. The findings support future research with stronger study design and larger sample size for the safety comparison between colistin and polymyxin B.

Dexpanthenol and ascorbic acid ameliorate colistin-induced nephrotoxicity in rats.

OBJECTIVE: Colistin is a potent antibiotic which is mainly preferred in the treatment of multidrug-resistant (MDR) gram-negative bacilli. However, due to the increased risk of acute kidney injury following its use, the clinical application is limited. This nephrotoxicity is known to be induced by oxidative stress and related inflammation. In this study on rats, potent antioxidants Dexpanthenol (DEX) and Ascorbic acid (Vit C) have been administered in combination with Colistin to find out whether they would weaken Colistin's nephrotoxic effects. MATERIALS AND METHODS: Inflammation biomarkers were studied with enzyme-linked immunosorbent assay (ELISA) kits, and oxidative stress biomarkers were studied with different photometric methods in blood and tissue samples taken after treatment with DEX and Vit C in rats with colistin nephrotoxicity. In addition, inflammation and necrosis in the kidney tissues were examined pathologically. RESULTS: It has been observed in the serum and tissue samples that DEX and Vit C decrease oxidative stress and inflammation biomarkers, therefore acting as nephroprotective agents. CONCLUSIONS: These compounds have been found to ameliorate the nephrotoxic effects of Colistin, which were demonstrated in the rats treated with Colistin, as well as the combinations.

Combination of colistin and tobramycin inhibits persistence of Acinetobacter baumannii by membrane hyperpolarization and down-regulation of efflux pumps.

Acinetobacter baumannii, a leading cause of nosocomial infections, is a serious health threat. Limited therapeutic options due to multi-drug resistance and tolerance due to persister cells have urged the scientific community to develop new strategies to combat infections caused by this pathogen effectively. Since combination antibiotic therapy is an attractive strategy, the effect of combinations of antibiotics, belonging to four classes, was investigated on eradication of persister cells in A. baumannii. Among the antibiotics included in the study, tobramycin-based combinations were found to be the most effective. Tobramycin, in combination with colistin or ciprofloxacin, eradicated persister cells in A. baumannii in late exponential and stationary phases of growth. Mechanistically, colistin facilitated the entry of tobramycin into cells by increasing membrane permeability and inducing hyperpolarization of the inner membrane accompanied by increase in ROS production. Expression of the genes encoding universal stress protein and efflux pumps was down-regulated in response to tobramycin and colistin, suggesting increased lethality of their combination that might be responsible for eradication of persister cells. Thus, a combination of tobramycin and colistin could be explored as a promising option for preventing the relapse of A. baumannii infections due to persister cells.

Intravenous colistin for the management of multidrug-resistant bacterial infections in Indian patients.

Multidrug-resistant Gram-negative bacterial infection is a serious global concern and especially in low and middle-income countries (LMIC) such as India. Colistin, an antimicrobial once abandoned following reports of organ toxicity, has re-emerged as an essential therapeutic agent in the management of these infections. A retrospective review of 162 inpatients was done, focusing on culture-proven multidrug-resistant infections requiring colistin. The overall clinical outcome in 58% of patients was found to be good, with nephrotoxicity and neurotoxicity occurring only in 8 (5%) and 4 (2.5%) patients, respectively. Multivariate analysis revealed an elevated lactate and raised urea to be independent factors associated with poor clinical response. In conclusion, there appears to be strong evidence supporting the use of colistin in the management of multidrug-resistant Gram-negative bacterial infections.

Effects of Different Component Contents of Colistin Methanesulfonate on the Pharmacokinetics of Prodrug and Formed Colistin in Human.

PURPOSES: To evaluate the effects of component contents in different colistin methanesulfonate (CMS) formulas on their clinical pharmacokinetics of the prodrug CMS and the formed colistin. METHODS: Two CMS formulas (CTTQ and Parkedale) were investigated in a single dose, randomized, open-label, crossover study conducted in 18 healthy Chinese subjects. Both CMS formulas met the requirements of European Pharmacopoeia 9.2 with 12.1% difference in the two major active components (CMS A and CMS B). The PK parameters after a single intravenous infusion of CMS at 2.5 mg/kg were calculated and the steady-state plasma colistin concentrations (Css,avg) following multiple dosing, once every 12 h for 7 days, were simulated with the non-compartment model. RESULTS: The systemic exposure (AUC0-inf) of CMS were 59.49 ± 5.90 h·µg/mL and 51.09 ± 4.70 h·µg/mL, and the AUC0-inf of colistin were 15.39 ± 2.63 h·µg/mL and 12.36 ± 2.10 h·µg/mL for CTTQ and Parkedale, respectively. The ratios (90% CI) of geometric mean of AUC0-inf of CTTQ to Parkedale were 116.38% (112.95%, 119.91%) and 124.49% (120.76%, 128.35%) for CMS and colistin, respectively. The predicted Css,avg (95% CI) were 0.92 (0.85, 0.99) µg/mL and 0.74 (0.69, 0.79) µg/mL for CTTQ and Parkedale, respectively. CONCLUSION: The difference in component content in the two CMS formulas had a significant (P < 0.001) impact on the systemic exposure of colistin in human, thus, warranted essential considerations in clinical applications.