Dose Of Colistin Research Articles

Gelofusine Ameliorates Colistin-Induced Nephrotoxicity.

Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologically. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

Chronic kidney disease after acute kidney injury associated with intravenous colistin use in survivors of severe infections: A comparative cohort study

PurposeThe use of colistin for multi-drug resistant (MDR) infections has led to an increase of colistin-associated acute kidney injury (AKI). Nevertheless, information on long-term renal prognosis is scarce. We aimed to determine the predictors of chronic kidney disease (CKD) in survivors of MDR-infections with colistin-associated AKI. MethodsA retrospective cohort of patients with colistin-associated AKI was compared with controls (survivors of severe infections who developed AKI matched by age, sex, diabetes, vancomycin exposure, and baseline kidney function). The primary outcome was the development of CKD after 6months of follow-up. ResultsFrom 2011 to 2015, 122 patients with MDR infections received colistin. Among 72 survivors, 29 (40%) had colistin-associated AKI. After 6months, 22 of them (75%) progressed to CKD (G3 in 21/22) compared with 16 (27%) in 58 controls (P<0.001). Independent predictors of progression to CKD were colistin use [odds ratio (OR): 8.86; 95% CI: 2.8–27.8] and age (OR: 1.04, 95% CI: 1.01–1.07). In patients exposed to colistin, a total dose of colistin >5g was an independent predictor of progression to CKD (OR: 14.1, 95% CI: 2.6–75.7). ConclusionColistin-associated AKI had a substantial risk for the latter development CKD, and consequently, these patients should be tightly monitored.

The 21st-century challenge to neurocritical care: the rise of the superbug Acinetobacter baumannii. A meta-analysis of the role of intrathecal or intraventricular antimicrobial therapy in reduction of mortality.

OBJECTIVE Neurosurgical infections due to multidrug-resistant organisms have become a nightmare that neurosurgeons are facing in the 21st century. This is the dawn of the so-called postantibiotic era. There is an urgent need to review and evaluate ways to reduce the high mortality rates due to these infections. The present study evaluates the efficacy of combined intravenous plus intrathecal or intraventricular (IV + IT) therapy versus only intravenous (IV) therapy in treating postneurosurgical Acinetobacter baumannii infections. METHODS The authors performed a meta-analysis of all peer-reviewed studies from the PubMed, Cochrane Library database, ScienceDirect, and EMBASE in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Five studies were finally included in the present analysis: 126 patients were studied who had postneurosurgical A. baumannii infection. The Cochrane collaboration tool was used to evaluate risk of bias, and a test of heterogeneity was performed. The I2 statistic was calculated. The patients were divided into 2 groups: the IV group received only intravenous therapy and the IV + IT group received both intravenous and intrathecal or intraventricular antimicrobial therapy. The outcome was mortality attributed specifically to A. baumannii infection in postneurosurgical cases. The pooled data were analyzed using the Cochran-Mantel-Haenszel method in a fixed-effects model. RESULTS The total number of patients in the IV-only group was 73, and the number of patients in the IV + IT group was 53. The mean duration of intravenous therapy was 27 days. The mean duration of intrathecal colistin was 21 days. The intravenous dose of colistin ranged from 3.75 to 8.8 MIU per day. The dose of intrathecal colistin ranged between 125,000 and 250,000 IU per day. The overall calculated odds ratio for mortality for the IV + IT group after pooling the data was 0.16 (95% CI 0.06-0.40, p < 0.0001). The patients who received IV + IT therapy had an 84% lower risk of dying due to the infection compared with those who received only IV therapy. CONCLUSIONS There is an 84% lower risk of mortality in patients who have been treated with combined intrathecal or intraventricular plus intravenous antimicrobial therapy versus those who have been treated with intravenous therapy alone. The intrathecal or intraventricular route should be strongly considered when dealing with postneurosurgical multidrug-resistant A. baumannii infections.

The combined use of tigecycline with high-dose colistin might not be associated with higher survival in critically ill patients with bacteraemia due to carbapenem-resistant Acinetobacter baumannii

ObjectiveTo assess the association of survival and treatment with colistin and tigecycline in critically ill patients with carbapenem-resistant Acinetobacter baumannii bacteraemia. MethodsAn observational cohort study was carried out. Targeted therapy consisted of monotherapy with colistin (9 million UI/day) or combined therapy with colistin and tigecycline (100 g/day). The primary outcome was 30-day crude mortality. The association between combined targeted therapy and mortality was controlled for empirical therapy with colistin, propensity score of combined therapy and other potential confounding variables in a multivariate Cox regression analysis. ResultsA total of 118 cases were analysed. Seventy-six patients (64%) received monotherapy and 42 patients (36%) received combined therapy. The source of bacteraemia was primary in 18% (21/118) of the patients, ventilator-associated pneumonia in 64% (76/118) and other sources in 14% (16/118). The 30-day crude mortality rate was 62% (42/76) for monotherapy and 57% (24/42) for combined therapy. The variables associated with 30-day crude mortality were: Charlson index (hazard ratio (HR) 1.16, 95% CI 1.02–1.32; p 0.028), empirical therapy with colistin (HR 2.25, 95% CI 1.33–3.80; p 0.003) and renal dysfunction before treatment (HR 1.91, 95% CI 1.01–3.61; p 0.045). Combined targeted therapy was not associated with lower adjusted 30-day crude mortality (adjusted HR 1.29, 95% CI 0.64–2.58; p 0.494). ConclusionsCombined targeted therapy with high-dose colistin and standard dose tigecycline was not associated with lower crude mortality of bacteraemia due to carbapenem-resistant A. baumannii in critically ill patients. Trial registrationRegistered in ClinicalTrials.gov. Identifier: NCT02573064.

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria

Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.

Colistin nephrotoxicity in the ICU: Is it different in the geriatric patients?

Most significant side effect of colistin therapy which is used for the treatment of multi-drug resistant Gram-negative infections is nephrotoxicity. Our aim was to investigate the differences of colistin nephrotoxicity between the geriatric age group (≥65years) and the younger age group (<65years) in critically ill medical intensive care unit (ICU) patients. The medical records of the 76 patients who were taken colistin therapy due to multi-resistant Gram-negative infections between January 2010 and June 2014 in the our medical ICU were retrospectively investigated. Demographic characteristics, reasons for colistin use, daily colistin dose, duration of colistin use were recorded. Colistin-dependent renal dysfunction was evaluated according to the risk, injury, failure, loss and end-stage renal failure (RIFLE) criterias. The median age of the patients was 65 (65.8% male). Nephrotoxicity was developed in 36 (47.4%) patients. Thirty-nine (51.3%) patients were in geriatric age group, 37 (48.7%) were in younger age group. In geriatric age group, the rates of male gender (53.8 vs 78.4%, p = 0.031), pulmonary (48.7 vs 16.2%, p = 0.003) and cardiac diseases (71.8 vs 29.7%, p < 0.001), post-nephrotoxicity BUN levels (p = 0.023) and urine output during nephrotoxicity (p = 0.016) were higher than younger age group. Nephrotoxicity was developed in 22 (56.4%) patients of geriatric age group, and in 14 (37.8%) patients in younger age group (p = 0.115). The presence of cardiac disease, renal pathology and high creatinin value on admission, daily amount of colistin per body mass, total amount of colistin, use of colistin for pulmonary infection, use of amphotericin and vasopressor on admission were found as risk factors for colistin nephrotoxicity development in all study group; the daily amount of colistin per body mass (risk ratio:0.41; 95% CI 0.19-0.89) and vasopressor use during hospitalization were found independent risk factors (risk ratio:13.54; 95% CI 2.21-83.09). In our study, in geriatric patient group colistin nephrotoxicity was not different from the younger age group. In the ICU, the age for nephrotoxicity does not appear to be a point to be considered for the initiation of colistin.

Evaluating Adherence of Health-Care Team to Standard Guideline of Colistin Use at Intensive Care Units of a Referral Hospital in Shiraz, Southwest of Iran.

Purpose: To evaluate colistin use according to global standard drug consumption in intensive care units of a referral hospital in Shiraz, IranMethods: A prospective, interventional study was performed during an 11 month period on 100 patients admitted to ICUs of a teaching hospital being treated with colistin for at least 3 subsequent doses. Required demographic, clinical, and paraclinical data were gathered by a pharmacist. Fifteen indexes were considered to evaluate colistin use. A clinical pharmacist reviewed indication and dose of colistin at the time of prescribing this agent.Results: In our study population, pneumonia (69%) was the main indication of colistin. In 87% of patients, colistin administration was based on microbiological laboratory evidence. Continuation of therapy was inappropriate in 5% of cases. By the intervention of the clinical pharmacist, colistin was discontinued in all patients in whom empirical therapy was continued incorrectly. None of the patients received loading dose of colistin. The maintenance dose, dose interval, and duration of treatment of colistin were appropriate in 76%, 71%, and 100% of patients, respectively. For none of the patients, the pharmacokinetic dosing method was used. In all patients, serum creatinine and WBC count were evaluated on daily basis. The sum indexes of colistin use were relevant to standard guidelines in 67.33% of the cases.Conclusion: The results of this study highlight the necessity of the pharmaceutical care team participation in all stages of treatment with antibiotics. After pharmacist interventions, some criteria of colistin utilization were corrected and brought closer to standard values.

Clinical outcomes and nephrotoxicity of colistin loading dose for treatment of extensively drug-resistant Acinetobacter baumannii in cancer patients.

BackgroundColistin is a last-line defense therapy against extensively drug-resistant Acinetobacter baumannii (XDR-AB). Despite a loading dose of colistin being applied in many clinical practices, studies evaluating the effect of the loading dose of colistin in cancer patients remain limited.Patients and methodsA retrospective cohort study of cancer patients who received either a loading or non-loading dose of colistin for treatment of XDR-AB was conducted. For each group, the clinical response, bacteriological eradication and serum creatinine were recorded. Logistic regression was applied to evaluate the effects of therapy on each of the three aforementioned outcomes.ResultsOne hundred and two patients diagnosed with XDR-AB infections between January 2012 and December 2015 were recruited. Only 75 patients were given a loading dose of colistin. There was no significant clinical and microbiological response in patients in the loading dose group or patients in the non-loading dose group. However, 38 (50.67%) patients in the loading dose group and 6 (22.22%) patients in the non-loading dose group developed nephrotoxicity according to the RIFLE criteria (p = 0.013). Multivariate logistic regression analysis showed that independent predictors of clinical response were Charlson score ≥4 and duration of colistin treatment ≥10 days. Septic shock correlated with both poor clinical and microbiological response. Independent predictors for nephrotoxicity were loading dose colistin and patient’s age ≥60 years.ConclusionAdministration of colistin loading dose did not significantly increase clinical response, microbiological response or mortality rate compared to non-loading dose in cancer patients with XDR-AB-related infections. However, nephrotoxicity was significantly higher when patients received loading dose colistin.

Efficacy and Safety of High Loading Dose of Colistin in Multidrug-Resistant Acinetobacter baumannii: A Prospective Cohort Study.

We aimed to assess the efficacy and safety of a high loading dose of colistin and no loading dose of colistin to treat multidrug-resistant (MDR) Acinetobacter baumannii infections. We conducted a prospective cohort study of patients with MDR A baumannii infections at a university-affiliated hospital from December 2014 to January 2016. In the high loading dose group, the patients received a high loading dose of 300 mg colistin base activity (CBA) followed by a maintenance dose of 150 mg CBA twice daily, and patients in the no loading dose group received only the maintenance dose. The primary outcome was clinical response. The secondary outcomes were 28-day mortality and microbiological response. A total of 255 cases were identified. The high loading dose of colistin strategy provided no significant difference in good clinical response when compared to the no loading dose group (65.5% vs 70.4%; P = .442), without a significant difference in the development of renal dysfunction (52.3% vs 49.4%; P = .664). However, microbiological eradication was significantly higher among patients who received the high loading dose of colistin when compared to those who received the no loading dose (87.9% vs 70.4%; P = .0006). The high loading dose of colistin strategy was effective and safe for treating patients with MDR A baumannii.

Nephrotoxicity of High and Conventional Dosing Regimens of Colistin: A Randomized Clinical Trial.

Nephrotoxicity has been a major long-standing concern about colistin.This study was designed to compare nephrotoxicity of high dose and conventional dose of colistin. A randomized open-labeled clinical trial on 40 patients with multi-drug resistant gram negative infections was designed. Patients were allocated into two equal-size groups receiving high (a loading dose of 9 million international units (MIU) and maintenance doses of 4.5 MIU every 12 h) and conventional dose (2 MIU every 8 h) of colistin. Blood samples were taken on day 1, 3, 5, 7 and 10 of treatment for measuring serum cystatin C (Cys C) levels. Incidence of acute kidney injury (AKI) was also evaluated based on RIFLE criteria. Mean ± sd of the difference between baseline and day 10 Cys C levels in high dose and conventional dose groups were 1.61 ± 0.90 and 1.32 ± 0.48, respectively (P = 0.30). Within group analysis showed increase in Cys C levels in both groups (P = 0.001),however, no significant difference in Cys C levels was seen in between groups analysis (P = 0.13). Prevalence of AKI based on RIFLE criteria was 60% and 15% in high dose and conventional dose groups, respectively (P = 0.003). Comparison of Cys C between AKI (mean ± sd) and non-AKI (mean ± sd) patients, irrespective of colistin dosage regimens, confirmed a significant difference (P < 0.0001). Although, colistin-induced nephrotoxicity, determined by Cys C levels, was not confirmed by our findings, however, higher incidence of AKI in high-dose group, defined by RIFLE criteria, along with higher levels of Cys C in AKI patients are supportive of the higher risk of renal toxicity associated with high-dose regimen of colistin. More RCTs with a larger sample size are recommended.

Safety and effectiveness of colistin compared with non-colistin combinations in the treatment of multi drug resistant bacterial infections

Background: Multi drug resistant (MDR) bacteria are usually defined as when it is resistant to three or more group of antibiotics. The objective of this study was to determine the efficacy and safety of colistin when compared with other antibiotics for the treatment of infections caused by MDR Acinetobacter baumannii and Pseudomonas aeruginosa.Methods: A single centre, prospective cohort study was conducted at Krishna Institute of medical Sciences, Hyderabad, India between September 2016 to March 2017. Seventy-four patients (74) were included in the study. Primary outcome were good clinical response and thirty days’ mortality, secondary outcome were microbiological response and adverse drug reactions of the drug.Results: A total of 74 patients were enrolled into the study. Forty patients (40) were received intravenous colistin dose of 2.5mg-5mg/kg/day. Remaining thirty-four patients (34) received other antibiotics which includes carbapenem, aminoglycosides. etc. The mean age, gender, underlying conditions and severity of illness of the patients in both groups were significantly same. In colistin group 27 (67.5%) patients and 11 (32.3%) patients had good clinical response. The overall mortality of the patients in the colistin group was 17.5% and that in the non-colistin group was 38.2%. The incidence of nephrotoxicity in colistin was 15% and 35.2% in non colistin group. No neurotoxicity was observed in present study.Conclusions: Our study concludes treatment with colistin decreases patient mortality and increase the clinical response in multidrug-resistant A. baumannii and P. aeruginosa infected patients. However large multicentric clinical trials are needed to demonstrate the safety and efficacy of colistin.

Good tolerability of high dose colistin-based therapy in patients with haematological malignancies.

Colistin is usually the only drug fully active against multi-drug resistant Gram-negative bacteria, but its nephrotoxicity might limit its use. Recent pharmacokinetic/pharmacodynamic data suggest that high dose of colistin, preceded by a loading dose, are needed to maximize its antibacterial effect. The aim of this study was to determine the safety of high doses colistin, in haematology population. A retrospective review of haematology patients who received high dose colistin-based therapy in years 2011-2016 was performed. Nephrotoxicity was assessed using RIFLE criteria. Thirty patients who received 38 courses of colistin were included in the study. Colistin was always administered together with other antibiotics. Colistin was well tolerated, with one case of neurological toxicity and one of cutaneous reaction. There were 22 (58%) treatment cycles without any nephrotoxicity, even though during 16 of these cycles other nephrotoxic drugs were administered. Severe (injury or failure) renal toxicity occurred during 6 (16%) treatment courses, requiring colistin discontinuation in 2 patients and colistin dose reduction in 1. Poorer renal function at baseline and younger age were the only variables associated with increased renal toxicity (p=0.011 and p=0.031, respectively). Overall mortality was 18% (7/38) and 29% (11/38) at 7 and 30days after the treatment onset. In adult haematology population, high dose colistin therapy is safe and efficacious, despite high frequency of concomitant nephrotoxic treatment.

High dose of antibiotic colistin induces oligomerization of molecular chaperone HSP90.

Colistin is an antimicrobial cationic peptide that belongs to the polymyxin family. Colistin was clinically used for the treatment of gram-negative infections but fell out of favour because of its significant side effects including neurotoxicity and nephrotoxicity. More recently, colistin has been regarded as one of the important options for nosocomial infections caused by multidrug resistant bacteria. Mechanisms of both the side effect onset of the drug and the side effect reduction are yet to be elucidated. In this study, we identified the specific binding protein of colistin using an affinity column chromatography. Colistin binds to the molecular chaperone HSP90. Although colistin slightly suppressed the chaperone activity of HSP90, there are no effects on the ATPase activity for a low concentration of colistin. Interestingly, colistin-induced aggregation of HSP90 via the N-domain. As for the cell viability of the SHSY5Y cell, the cell viability decreased to approximately 80% by the colistin 300 μM. However, the cell viability recovered to approximately 100% by adding ATP dosage. The same result was obtained by dot blot assay using anti-HSP90 antibody. Our results may help to understand the side effect mechanism of colistin.

Kolistin Dozuna Dikkat: Nadir Nörotoksik Yan Etkilerin Görüldüğü Bir Olgu Sunumu

Kolistin Dozuna Dikkat: Nadir Nörotoksik Yan Etkilerin Görüldüğü Bir Olgu Sunumu

Colistin loading dose enhanced antimicrobial activity for invivo mouse thigh infection model with Pseudomonas aeruginosa with highly antimicrobial resistant.

This is the first report to test the loading dosage of colistin against Pseudomonas aeruginosa, including MDRP. Using invivo murine thigh infection model, in the loading dosage regimen (Day 1:50mg/kg q12h, Day 2-3: 25mg/kg q12h) group, 5 to 6 log10CFU/ml reduction compared with control were observed for both strains of P.aeruginosa with colistin MIC 0.5 and 1μg/mL at 72h. But, similar reduction was observed for the strains with colistin MIC 0.5μg/mL only in normal dosage regimen (Day 1-3: 25mg/kg q12h) group. For P.aeruginosa with colistin MIC 1μg/mL, colistin loading dosage regimens showed greater antimicrobial activity than that of without loading dosage group (p<0.05). These data suggest that the colistin loading regimen would be one of the useful options for P.aeruginosa with antimicrobial resistance infection treatment.

In vitro and in vivo Pharmacodynamics of Colistin and Aztreonam Alone and in Combination against Multidrug-Resistant Pseudomonas aeruginosa

Background: Reports of Pseudomonas aeruginosa with high antimicrobial resistance have steadily emerged, threatening the utility of a mainstay in antipseudomonal therapy. This study evaluated the antimicrobial activities of various combination therapies against P. aeruginosa with high antimicrobial resistance, including multidrug-resistant P. aeruginosa (MDRP) using an in vitro and in vivo study. Methods: We evaluated 24 combination therapies, including colistin, aztreonam, meropenem, ceftazidime, ciprofloxacin, amikacin, rifampicin, arbekacin and piperacillin against 15 MDRP isolates detected at Aichi Medical University Hospital with the break-point checkerboard method. Based on the results of the in vitro study, we evaluated antimicrobial activity against highly antimicrobial-resistant P. aeruginosa with an in vivo murine thigh infection model. Results: The combination regimens including colistin and aztreonam showed higher antimicrobial activity against the 15 MDRP isolates. In the in vivo study, the high-dose colistin monotherapy (16 mg/kg every 12 h) achieved greater log₁₀ CFU changes than the normal-dose colistin regimen (8 mg/kg every 12 h) against 5 P. aeruginosa isolates, including 2 MDRP isolates (p < 0.05). Aztreonam monotherapy (400 mg every 8 h) yielded bacterial densities similar to untreated control mice for the MDRP isolate evaluated. The combination therapy with a higher dose of colistin had superior antimicrobial activity against 5 P. aeruginosa with colistin (MIC 0.5 μg/ml) and aztreonam (MIC ≥128 μg/ml) than colistin monotherapy. Conclusion: The data suggest that the combination treatment of colistin and aztreonam could be the most useful for treating highly resistant P. aeruginosa with a higher susceptibility to colistin, including MDRP infections.

Analysis of the Safety and Efficacy of a Colistin Dosing Guideline in the Management of Infections Caused by Multi-Drug Resistant Gram-negative Organisms

Analysis of the Safety and Efficacy of a Colistin Dosing Guideline in the Management of Infections Caused by Multi-Drug Resistant Gram-negative Organisms

The Effectiveness and Safety of High-Dose Colistin: Prospective Cohort Study.

Optimizing colistin dosing should translate to improved patient outcomes. We used data from 2 prospective cohort studies performed between 2006 and 2009 and between 2012 and 2015. In the latter period, a new policy of high-dose colistin (9 million international units [MIU] loading dose followed by 9 MIU daily for normal renal function) was introduced in 2 participating hospitals. We included adult inpatients with invasive infections caused by carbapenem-resistant gram-negative bacteria treated with colistin. Our primary exposure variable was colistin dose, dichotomized to high-dose vs other regimens. The primary outcome was 28-day mortality. We generated a propensity score for high-dose colistin and conducted propensity-adjusted multivariable and matched-cohort analyses for mortality. Of 529 consecutive patients fulfilling inclusion criteria, 144 were treated with high-dose colistin and 385 with lower-dose colistin regimens. The median daily dose in the high-dose group was 9 MIU (interquartile range [IQR], 9-9) vs 4 MIU (IQR, 3-6) with other regimens. There were 50 of 144 (34.7%) deaths with high-dose colistin vs 165 of 385 (42.9%) with low-dose colistin (P = .1). The propensity-adjusted odds ratio (OR) for mortality was 1.07 (95% confidence interval [CI], .63-1.83) for high-dose colistin. Similar results were obtained when using the study period as the exposure variable, in the subgroup of bacteremic patients (n = 207) and in the propensity-matched cohort (OR, 1.11 [95% CI, .67-1.82]). Nephrotoxicity (RIFLE injury or higher; OR, 2.12 [95% CI, 1.29-3.48]; n = 396) and seizures were significantly more common with high-dose colistin. In a large cohort, we found no association between high colistin dosing and all-cause mortality. High dosing was associated with more nephrotoxicity.

Challenge for higher colistin dosage in critically ill patients receiving continuous venovenous haemodiafiltration

Traditionally, reduced daily doses of colistin methanesulphonate (CMS) in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF) have resulted in suboptimal colistin concentrations. The necessity of a loading dose (LD) at treatment initiation has been proposed. A LD of 9 million IU (MU) [ca. 270 mg of colistin base activity (CBA)] was administrated with a maintenance dose of 4.5 MU (ca. 140 mg CBA) every 12 h (q12h) to eight critically ill patients receiving renal replacement therapy. Blood samples were collected immediately before and at different time intervals after the LD and the fourth dose, whilst pre-filter and post-filter blood samples were also collected. CMS and colistin concentrations were determined using an LC-MS/MS assay. Median maximum observed concentrations after the LD were 22.1 mg/L for CMS and 1.55 mg/L for colistin, whereas during maintenance dosing the corresponding values were 12.6 mg/L and 1.72 mg/L, respectively. CVVHDF clearance was determined as 2.98 L/h for colistin, equivalent to 62% of total apparent colistin clearance in CVVHDF patients. Both CMS and colistin were cleared by CVVHDF. Application of a LD of 9 MU CMS resulted in more rapid achievement of the target colistin concentration. Following implementation of a predicted pharmacokinetic model on plasma CMS/colistin concentrations, a LD of 12 MU CMS appears more appropriate, whilst a CMS maintenance dosage of at least 6.5–7.5 MU q12h is suggested in patients undergoing CVVHDF. However, further clinical studies are warranted to assess the safety of a LD of 12 MU CMS in patients receiving CVVHDF.

Predictors of mortality in patients with extensively drug-resistant Acinetobacter baumannii pneumonia receiving colistin therapy

The ratio of the area under the free (unbound) concentration–time curve to minimum inhibitory concentration (fAUC/MIC) was proposed to be the pharmacokinetic/pharmacodynamic index most strongly linked to the antibacterial effect of colistin against Acinetobacter baumannii. A retrospective study of patients who received colistin to treat pneumonia caused by extensively drug-resistant (XDR) A. baumannii over a 4-year period was performed to assess the impact of the colistin MIC on mortality. A total of 227 patients were included in the analysis. The 7-day and 14-day mortality rates of patients with XDR A. baumannii pneumonia receiving colistin therapy were 15.0% and 23.8%, respectively. In the multivariate analysis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, days from index culture to first dose of colistin, underlying tumour and septic shock at presentation were independent predictors of mortality in patients with XDR A. baumannii pneumonia receiving colistin therapy. In the univariate analysis, the colistin dose based on ideal body weight (IBW) correlated with patient outcome. Therefore, the use of IBW appeared to be more appropriate to calculate the colistin dosage. In addition, these results highlight the clinical significance of colistin MIC in patients with XDR A. baumannii pneumonia receiving colistin therapy. Although MICs were in the ‘susceptible’ range, patients infected with isolates with high colistin MICs showed a poorer clinical response rate than patients infected with isolates with low colistin MICs. Further clinical studies are needed to evaluate the roles of colistin MIC for predicting mortality in XDR A. baumannii pneumonia with a high colistin MIC.