Colistin Treatment Research Articles

Association between colistin dose and development of nephrotoxicity.

To investigate the development of nephrotoxicity associated with colistin dose, and whether this relationship differs depending on renal function. A retrospective cohort study of patients who received intravenous colistin to treat infections caused by extensively drug-resistant Gram-negative microorganisms. Adult patients receiving colistin for 72 hours or longer were included in this study. Patients who received renal replacement therapy at baseline or were administered colistin for less than 3 days were excluded. Colistin-induced nephrotoxicity was defined as a doubling of baseline serum creatinine. Colistin dosing was evaluated based on both actual body weight and ideal body weight. Single general hospital between 2010 and 2013. A total number of 475 patients received colistin therapy. Of these patients, 329 met the inclusion criteria and were included in the analysis. None. One hundred forty-three patients (43.5%) experienced nephrotoxicity during colistin treatment. The median onset time of nephrotoxicity was 6 days (interquartile range, 4-8 days). The patients with nephrotoxicity were older. Hematocrit and serum albumin levels were lower in patients with nephrotoxicity. Median daily dosing of colistin based on ideal body weight was significantly higher in patients with nephrotoxicity than in those without nephrotoxicity (4.55 vs 4.43 mg/kg/d, respectively; p=0.021). The cumulative dose was not different between patients with and without nephrotoxicity. In multiple logistic regression analysis, daily colistin dosing based on ideal body weight was only significantly associated with the development of nephrotoxicity in patients with an estimated glomerular filtration rate<60 mL/min/1.73 m2 (odds ratio, 2.34; 95% CI, 1.22-4.5). In these affected patients, based on a receiver operating characteristic plot, the optimal predictive cutoff of colistin dose for the development of nephrotoxicity was 2.87 mg/kg/d of colistin, with a sensitivity of 92.3% and a specificity of 76.7%. In patients with estimated glomerular filtration rate≥60 mL/min/1.73 m, age, serum albumin, hematocrit, and use of glycopeptide were associated with the development of nephrotoxicity. Development of nephrotoxicity was significantly more strongly associated with the dose of colistin, but only in patients with an estimated glomerular filtration rate<60 mL/min/1.73 m2 and not in those with normal renal function.

Variables determining the development of colistin-associated renal impairment.

The aim of this study was to identify the predictors of acute renal injury associated with colistin treatment. The patients who received treatment with colistin for more than 3 days were included in this retrospective cohort study. Acute renal injury was defined by the RIFLE (Risk Injury Failure Loss End stage renal disease) criteria. Patients whose serum creatinine levels increased at least 1.5-fold compared with baseline value were considered as cases with renal injury. The independent variables determining the development of acute renal injury were investigated by survival analysis. A total of 112 cases [67 (59.8 %) were male, median age 64 (range: 18-93) years] were included in the study. Acute renal injury occurred in 66 (58.9 %) patients. Renal injury developed in first 7 days of the colistin therapy in 52 (78.8 %) cases and at day 8-23 in 14 (21.2 %) cases. On the day with highest levels of creatinine, 25 (22.3 %), 17 (15.2 %), and 33 (29.5 %) cases were in 'Risk', 'Injury', and 'Failure' group, respectively, according to RIFLE criteria. We identified three independent risk factors predicting acute colistin-induced renal injury: advanced age, low serum albumin levels, and high serum total bilirubin levels [odds ratio (confidence interval) = 1.022 (1.006-1.037), 0.643 (0.415-0.994), and 1.129 (1.014-1.257), respectively]. The advanced age, low serum albumin levels, and high serum total bilirubin levels are independent risk factors for colistin-induced nephrotoxicity.

Preliminary clinical study of the effect of ascorbic acid on colistin-associated nephrotoxicity.

Nephrotoxicity is a dose-limiting factor of colistin, a last-line therapy for multidrug-resistant Gram-negative bacterial infections. An earlier animal study revealed a protective effect of ascorbic acid against colistin-induced nephrotoxicity. The present randomized controlled study was conducted in 28 patients and aimed to investigate the potential nephroprotective effect of intravenous ascorbic acid (2 g every 12 h) against colistin-associated nephrotoxicity in patients requiring intravenous colistin. Thirteen patients received colistin plus ascorbic acid, whereas 15 received colistin alone. Nephrotoxicity was defined by the RIFLE classification system. Additionally, urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-d-glucosaminidase (NAG) were measured as markers of renal damage, and plasma colistin concentrations were quantified. The baseline characteristics, clinical features, and concomitant treatments of the patients in the two groups were comparable. The incidences of nephrotoxicity were 53.8% (7/13) and 60.0% (9/15) in the colistin-ascorbic acid group and the colistin group, respectively (P = 0.956; relative risk [RR], 0.9; 95% confidence interval, 0.47 to 1.72). In both groups, the urinary excretion rates of NGAL and NAG on day 3 or 5 of colistin treatment and at the end of colistin treatment were significantly higher than those at the respective baselines (P < 0.05). However, the urinary excretion rates of these biomarkers at the various times during colistin treatment did not differ significantly between the groups (P > 0.05). The plasma colistin concentrations in the two groups were not significantly different (P > 0.28). The clinical and microbiological outcomes and mortality of the patients in the two groups were not significantly different. This preliminary study suggests that ascorbic acid does not offer a nephroprotective effect for patients receiving intravenous colistin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01501968.).

Autophagy regulates colistin-induced apoptosis in PC-12 cells.

Colistin is a cyclic cationic polypeptide antibiotic with activity against multidrug-resistant Gram-negative bacteria. Our recent study demonstrated that colistin induces apoptosis in primary chick cortex neurons and PC-12 cells. Although apoptosis and autophagy have different impacts on cell fate, there is a complex interaction between them. Autophagy plays an important role as a homeostasis regulator by removing excessive or unnecessary proteins and damaged organelles. The aim of the present study was to investigate the modulation of autophagy and apoptosis regulation in PC-12 cells in response to colistin treatment. PC-12 cells were exposed to colistin (125 to 250 μg/ml), and autophagy was detected by visualization of monodansylcadaverine (MDC)-labeled vacuoles, LC3 (microtubule-associated protein 1 light chain 3) immunofluorescence microscopic examination, and Western blotting. Apoptosis was measured by flow cytometry, Hoechst 33258 staining, and Western blotting. Autophagosomes were observed after treatment with colistin for 12 h, and the levels of LC3-II gene expression were determined; observation and protein levels both indicated that colistin induced a high level of autophagy. Colistin treatment also led to apoptosis in PC-12 cells, and the level of caspase-3 expression increased over the 24-h period. Pretreatment of cells with 3-methyladenine (3-MA) increased colistin toxicity in PC-12 cells remarkably. However, rapamycin treatment significantly increased the expression levels of LC3-II and beclin 1 and decreased the rate of apoptosis of PC-12 cells. Our results demonstrate that colistin induced autophagy and apoptosis in PC-12 cells and that the latter was affected by the regulation of autophagy. It is very likely that autophagy plays a protective role in the reduction of colistin-induced cytotoxicity in neurons.

The transcriptomic response of Acinetobacter baumannii to colistin and doripenem alone and in combination in an in vitro pharmacokinetics/pharmacodynamics model.

Colistin remains a last-line treatment for MDR Acinetobacter baumannii and combined use of colistin and carbapenems has shown synergistic effects against MDR strains. In order to understand the bacterial responses to these antibiotics, we analysed the transcriptome of A. baumannii following exposure to each. RNA sequencing was employed to determine changes in the transcriptome following treatment with colistin and doripenem, both alone and in combination, using an in vitro pharmacokinetics (PK)/pharmacodynamics model to mimic the PK of both antibiotics in patients. After treatment with colistin (continuous infusion at 2 mg/L), >400 differentially regulated genes were identified, including many associated with outer membrane biogenesis, fatty acid metabolism and phospholipid trafficking. No genes were differentially expressed following treatment with doripenem (Cmax 25 mg/L, t1/2 1.5 h) for 15 min, but 45 genes were identified as differentially expressed after 1 h of growth under this condition. Treatment of A. baumannii with both colistin and doripenem together for 1 h resulted in >450 genes being identified as differentially expressed. More than 70% of these gene expression changes were also observed following colistin treatment alone. These data suggest that colistin causes gross damage to the outer membrane, facilitates lipid exchange between the inner and outer membrane and alters the normal asymmetric outer membrane composition. The transcriptional response to colistin was highly similar to that observed for an LPS-deficient strain, indicating that many of the observed changes are responses to outer membrane instability resulting from LPS loss.

Clinical efficacy and safety of colistin treatment in patients with pulmonary infection caused by Pseudomonas aeruginosa or Acinetobacter baumannii: a meta-analysis.

IntroductionThe aim of this study was to evaluate the efficacy and safety of colistin treatment in patients with pulmonary infection caused by Pseudomonas aeruginosa or Acinetobacter baumannii.Material and methodsThe relevant studies were identified through a search of public databases including PubMed, MEDLINE and EMBASE up to December 2012. A meta-analysis was conducted to compare the clinical response, mortality and renal damage of colistin (colistin group) versus other effective antibiotics (control group). The odds ratio (OR) was chosen as the effect size.ResultsA total of 9 studies were eventually identified. The result of the meta-analysis showed that the pooled OR of clinical response was 1.24 (95% CI = 0.68–2.27, p > 0.05) for patients in the colistin group versus the control group, indicating no significant difference in efficacy between colistin and control groups. Similar results were obtained by the further subgroup meta-analyses by sample size, research year, ethnicity and study method. Treatment with colistin versus other agents did not affect hospital mortality (OR = 1.05, 95% CI = 0.58–1.89, p > 0.05) or renal damage (OR = 1.25, 95% CI = 0.78–2.00, p > 0.05). The combined estimate of our analysis was strong across multiple sensitivity analyses and without significant publication bias.ConclusionsOur results suggest that colistin may be as efficacious and safe as standard antibiotics for the treatment of pulmonary infection.

Çocuklarda İntravenöz Kolistin Kullanımı: Tek Merkez Deneyimi

Objective: Colistin, a bactericidal antibiotic, was used in the 1960s for the treatment of infections by gram-negative bacteria. Because of its side effects and the development of safer drugs, its use was abandoned in the 1980s. In infections within clinics where multi-drug-resistant gram-negative bacteria (MDRGNB) (especially Pseudomonas spp. and Acinetobacter spp.) are present, colistin usage is suggested if there is drug resistance to any other antibiotics. Nephrotoxicity is one of the commonly observed adverse effects following intravenous (IV) administration of colistin. Nephrotoxicity is dose-dependent and reversible. The aim of this study is to evaluate the efficacy and safety of colistin in MDRGNB infections occurring in pediatric and neonatal patients. Material and Methods: The files of all patients under the age of 18 who were given IV colistin treatment, apart from inhaler treatments, were retrospectively investigated. Demographic characteristics of patients, risk factors for systemic infection, causative microorganisms, and susceptibilities and side effects of colistin were evaluated. Results: Twenty-three patients meeting the criteria were included in the study. The median age was 2 years (4 days-17 years). Colistin was used for infections caused by MDR Acinetobacter baumannii 78.2% (18/23) and MDR Pseudomonas aeruginosa 21.8% (5/23). MDR A. baumannii was found growing in the blood cultures of 15 patients and in the urine, wound, and respiratory sample of 1 patient. MDR P. aeruginosa was found in respiratory samples of 4 patients and the blood culture of 1 patient. The duration of treatment with colistin was a median of 13 (4-30) days. All patients were given additional antibiotics with colistin. The most commonly used antibiotics were carbapenems (13 patients), with 5 patients given sulbactam-ampicillin, 4 given ciprofloxacin, and 3 given aminoglycoside. One patient died during treatment with colistin. No patient developed nephrotoxicity or neurotoxicity. Conclusion: It appears that IV colistin use is effective and safe for MDRGNB treatment in pediatric patients. (J Pediatr Inf 2014; 8: 153-8)

In vivo activity of daptomycin/colistin combination therapy in a Galleria mellonella model of Acinetobacter baumannii infection

Antimicrobial treatment of multidrug-resistant Acinetobacter baumannii (MDR-AB) infections continues to pose significant challenges. With limited options, clinicians have been pushed towards using unorthodox combinations of licensed antibiotics. Although daptomycin/colistin combination appears to be a promising treatment option based on in vitro data, further preclinical work is needed. In this study, the A. baumannii–Galleria mellonella system was employed to study the in vivo efficacy of this combination in order to determine whether it should be explored further for the treatment of MDR-AB infections. The antimicrobial activity of colistin alone and in combination with daptomycin was assessed versus an A. baumannii type strain (ATCC 19606) and a MDR-AB clinical strain (GN2231) isolated in Anhui, China. Synergy studies were performed using the microtitre plate chequerboard assay and time–kill methodology. The in vivo activity of daptomycin/colistin combination was assessed using a G. mellonella larvae model. The combination of daptomycin and colistin was bactericidal against both strains tested. In chequerboard assays, daptomycin was highly active against A. baumannii when combined with colistin [fractional inhibitory concentration index (FICI) of <0.5]. Treatment of G. mellonella larvae infected with lethal doses of A. baumannii resulted in significantly enhanced survival rates when daptomycin was given with colistin compared with colistin treatment alone (P<0.05). This work suggests that daptomycin/colistin combination is highly active against A. baumannii both in vitro and in a simple invertebrate model of infection.

Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis.

Respiratory tract infection with Pseudomonas aeruginosa occurs in most people with cystic fibrosis. Once chronic infection is established, Pseudomonas aeruginosa is virtually impossible to eradicate and is associated with increased mortality and morbidity. Early infection may be easier to eradicate.This is an update of a Cochrane review first published in 2003, and previously updated in 2006 and 2009. To determine whether antibiotic treatment of early Pseudomonas aeruginosa infection in children and adults with cystic fibrosis eradicates the organism, delays the onset of chronic infection, and results in clinical improvement. To evaluate whether there is evidence that a particular antibiotic strategy is superior to or more cost-effective than other strategies and to compare the adverse effects of different antibiotic strategies (including respiratory infection with other micro-organisms). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 08 September 2014. We included randomised controlled trials of people with cystic fibrosis, in whom Pseudomonas aeruginosa had recently been isolated from respiratory secretions. We compared combinations of inhaled, oral or intravenous antibiotics with placebo, usual treatment or other combinations of inhaled, oral or intravenous antibiotics. We excluded non-randomised trials, cross-over trials, and those utilising historical controls. Both authors independently selected trials, assessed risk of bias and extracted data. The search identified 49 trials; seven trials (744 participants) with a duration between 28 days and 27 months were eligible for inclusion. Three of the trials are over 10 years old and their results may be less applicable today given the changes in standard treatment. Some of the trials had low numbers of participants and most had relatively short follow-up periods; however, there was generally a low risk of bias from missing data. In most trials it was difficult to blind participants and clinicians to treatment given the interventions and comparators used. Two trials were supported by the manufacturers of the antibiotic used.Evidence from two trials (38 participants) at the two-month time-point showed treatment of early Pseudomonas aeruginosa infection with inhaled tobramycin results in microbiological eradication of the organism from respiratory secretions more often than placebo, odds ratio 0.15 (95% confidence interval 0.03 to 0.65) and data from one of these trials, with longer follow up, suggested that this effect may persist for up to 12 months.One randomised controlled trial (26 participants) compared oral ciprofloxacin and nebulised colistin versus usual treatment. Results after two years suggested treatment of early infection results in microbiological eradication of Pseudomonas aeruginosa more often than no anti-pseudomonal treatment, odds ratio 0.12 (95% confidence interval 0.02 to 0.79).One trial comparing 28 days to 56 days treatment with nebulised tobramycin solution for inhalation in 88 participants showed that both treatments were effective and well-tolerated, with no notable additional improvement with longer over shorter duration of therapy. However, this trial was not powered to detect non-inferiority or equivalence .A trial of oral ciprofloxacin with inhaled colistin versus nebulised tobramycin solution for inhalation alone (223 participants) failed to show a difference between the two strategies, although it was underpowered to show this. A further trial of inhaled colistin with oral ciprofloxacin versus nebulised tobramycin solution for inhalation with oral ciprofloxacin also showed no superiority of the former, with increased isolation of Stenotrophomonas maltophilia in both groups.A recent, large trial in 306 children aged between one and 12 years compared cycled nebulised tobramycin solution for inhalation to culture-based therapy and also ciprofloxacin to placebo. The primary analysis showed no difference in time to pulmonary exacerbation or proportion of Pseudomonas aeruginosa positive cultures. An analysis performed in this review (not adjusted for age) showed fewer participants in the cycled therapy group with one or more isolates of Pseudomonas aeruginosa, odds ratio 0.51 (95% CI 0.31 to 0.28). We found that nebulised antibiotics, alone or in combination with oral antibiotics, were better than no treatment for early infection with Pseudomonas aeruginosa. Eradication may be sustained for up to two years. There is insufficient evidence to determine whether antibiotic strategies for the eradication of early Pseudomonas aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. Four trials of two active treatments have failed to show differences in rates of eradication of Pseudomonas aeruginosa. There have been no published randomised controlled trials that investigate the efficacy of intravenous antibiotics to eradicate Pseudomonas aeruginosa in cystic fibrosis. Overall, there is still insufficient evidence from this review to state which antibiotic strategy should be used for the eradication of early Pseudomonas aeruginosa infection in cystic fibrosis.

Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway.

Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

In vivo evolution to colistin resistance by PmrB sensor kinase mutation in KPC-producing Klebsiella pneumoniae is associated with low-dosage colistin treatment.

Colistin is a key drug for the treatment of infections caused by extensively drug-resistant strains of Enterobacteriaceae producing carbapenemases. However, the emergence of colistin resistance is being increasingly reported, especially among Klebsiella pneumoniae strains producing KPC-type carbapenemases (KPC-KP). In this work, we investigated colistin-susceptible (KPB-1) and colistin-resistant (KPB-2) sequential isolates obtained from a patient with a KPC-KP infection before and after low-dosage colistin treatment, respectively. By using a next-generation sequencing approach and comparative genomic analysis of the two isolates, we detected in KPB-2 a nonsynonymous nucleotide substitution in the gene encoding the PmrB sensor kinase, resulting in a leucine-to-arginine substitution at amino acid position 82. Compared with KPB-1, KPB-2 exhibited upregulated transcription of pmrA and of pmrK, which is part of the pmrHFIJKLM operon responsible for modification of the colistin lipopolysaccharide target. Complementation with wild-type pmrB in KPB-2 restored colistin susceptibility and reduced the transcription of pmrA and pmrK to basal levels, while expression of PmrB(L82R) in KPB-1 did not alter colistin susceptibility or upregulate pmrA and pmrK expression, confirming the dominance of wild-type PmrB versus the PmrB(L82R) mutant. The present results indicated that PmrB mutations mediating colistin resistance may be selected during low-dosage colistin treatment. The colistin-resistant phenotype of KPB-2 was stable for up to 50 generations in the absence of selective pressure and was not associated with a significant fitness cost in a competition experiment.

Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum pathways.

Nephrotoxicity is the dose-limiting factor for colistin, but the exact mechanism is unknown. This study aimed to investigate the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in colistin-induced nephrotoxicity. Mice were intravenously administered 7.5 or 15 mg of colistin/kg of body weight/day (via a 3-min infusion and divided into two doses) for 7 days. Renal function, oxidative stress, and apoptosis were measured. Representative biomarkers involved in the mitochondrial, death receptor, and endoplasmic reticulum pathways were investigated, and the key markers involved in apoptosis and autophagy were examined. After 7-day colistin treatment, significant increase was observed with blood urea nitrogen, serum creatinine, and malondialdehyde, while activities of superoxide dismutase (SOD) and catalase decreased in the kidneys. Acute tubular necrosis and mitochondrial dysfunction were detected, and colistin-induced apoptosis was characterized by DNA fragmentation, cleavage of poly(ADP-ribose) polymerase (PARP-1), increase of 8-hydroxydeoxyguanosine (8-OHdG), and activation of caspases (caspase-8, -9, and -3). It was evident that colistin-induced apoptosis involved the mitochondrial pathway (downregulation of Bcl-2 and upregulation of cytochrome C [cytC] and Bax), death receptor pathway (upregulation of Fas, FasL, and Fas-associated death domain [FADD]), and endoplasmic reticulum pathway (upregulation of Grp78/Bip, ATF6, GADD153/CHOP, and caspase-12). In the 15-mg/kg/day colistin group, expression of the cyclin-dependent kinase 2 (CDK2) and phosphorylated JNK (p-JNK) significantly increased (P < 0.05), while in the 7.5-mg/kg/day colistin group, a large number of autophagolysosomes and classic autophagy were observed. Western blot results of Beclin-1 and LC3B indicated that autophagy may play a protective role in colistin-induced nephrotoxicity. In conclusion, this is the first study to demonstrate that all three major apoptosis pathways and autophagy are involved in colistin-induced nephrotoxicity.

ABSTRACT 431

Background and aims: Colistin is active against most multidrug-resistant, aerobic Gram-negative bacteria. Aims: The aim of this study is to document the clinical characteristics and outcomes of use of colistin in pediatric patients at a pediatric intensive care unit for the treatment of Ventilator Associated Pneumonia caused by Multi-Drug Resistant Acinetobacter Baumannii. Methods: We reviewed the medical and laboratory records of 5 critically ill children who were treated with colistin for 10 courses between January 2013 and December 2013 at the Pediatric Intensive Care Unit. Results: The median dosage of colistin was 4 mg/kg/d (ranging from 3 to 5 mg/kg/d, IQR 1) and duration of colistin therapy was changing from 10 days to 34 days. Thirty colistin treatment episodes (79%) had a good or partial clinical response and 8 (21%) had a poor clinical response. There was no evidence of neurotoxicity or nephrotoxicity in this study. All episodes responded colistin therapy however 2 patients died due to the septic shock which was not attributable to Multi-Drug Resistant Acinetobacter Baumannii infections. Conclusions: This small cohort study suggests that colistin is well tolerated and efficacious in severe nosocomial Ventilator Associated Pneumonia caused by Acinetobacter Baumannii.

In vivo emergence of colistin resistance in Acinetobacter baumannii clinical isolates of sequence type 357 during colistin treatment

This study was performed to investigate the mechanisms of in vivo acquisition of colistin resistance in A. baumannii during colistin treatment. Three colistin-susceptible/resistant pairs of A. baumannii were recovered from patients who underwent colistin treatment. All of the 6 isolates included in this study shared an identical sequence type (ST), ST375, and they showed identical SmaI-macrorestriction patterns by pulsed-field gel electrophoresis. The individual colistin-resistant isolates harbored distinct mutations in the pmrB gene. Mutations detected in the pmrB gene were Ala227Val, Pro233Ser, and frame shift from Phe26. In matrix-assisted laser desorption ionization–time of flight analysis, colistin-resistant isolates were different from their colistin-susceptible counterparts, and they showed additional distinct peaks at 1852 m/z, 1937 m/z, 1954 m/z, 1975 m/z, 2034 m/z, and 2157 m/z. In vivo selection of colistin-resistant A. baumannii occurred independently in strains of ST357 during colistin treatment, and the strains acquired colistin resistance via mutations in the pmrB gene resulting in modification of lipid A components.

CP-143 Evaluation of inhaled colistin treatment in patients without cystic fibrosis

BackgroundInhaled colistin (IC) is formally indicated to treat Pseudomonas aeruginosa bronchial infections in cystic fibrosis (CF) patients. In patients without CF it is not indicated and must be prescribed off-label...

The Use of Colistin in Critically Ill Children in a Pediatric Intensive Care Unit

Colistin is active against most multidrug-resistant, aerobic Gram-negative bacteria. Because of the reported nephrotoxicity during the first years of use of colistin, there were concerns of its use in pediatrics where there was limited experience The aim of this study is to document the clinical characteristics and outcomes of use of colistin in pediatric patients at a pediatric intensive care unit in Turkey. We reviewed the medical and laboratory records of 29 critically ill children who were treated with colistin for 38 courses between January 2011 and December 2011 at the Department of Pediatric Intensive Care Unit in Ankara University Medical School, Turkey. The median age was 17 months (range 3-217 months). Male-to-female ratio was 1:1.37. Ventilator-associated pneumonia (21 courses) was the leading diagnosis followed by catheter-related blood stream infection (6 courses), bacteremia (4 courses), ventriculoperitoneal shunt infection, peritonitis and pneumonia (1 course). The most commonly isolated microorganisms were Acinetobacter baumanni, Pseudomonas aeruginosa, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia, and Enterobacter cloacae. Two colistin formulations were used. Colimycin (Kocak Farma) was used in 21 colistin treatment episodes. The median dosage of colistin in this group was 5.0 mg/kg/d (2.3-5.6 mg/kg/d). Colomycin (Forest Laboratories) was used in 17 colistin treatment episodes. The median dosage of colistin in the second group was 75,000 International Unit/kg/d (50,000-80,000 International Unit/kg/d). Thirty colistin treatment episodes (79%) had a good or partial clinical response and 8 (21%) had a poor clinical response. Of the 8 colistin treatment episodes with poor clinical response, 3 were in the Colimycin group and 5 were in the Colomycin group. Ten patients died. There was no evidence of neurotoxicity in this study. Nephrotoxicity was observed in 1 patient but was not attributed to colistin because the patient had multiorgan failure at the same time. This study in a small cohort of patients suggests that the use of colistin in severe nosocomial infections caused by multidrug-resistant Gram-negative bacteria is well-tolerated and efficacious.

Effect of Aerosolized Colistin as Adjunctive Treatment on the Outcomes of Microbiologically Documented Ventilator-Associated Pneumonia Caused by Colistin-Only Susceptible Gram-Negative Bacteria

The increasing frequency of ventilator-associated pneumonia (VAP) caused by colistin-only susceptible (COS) gram-negative bacteria (GNB) is of great concern. Adjunctive aerosolized (AS) colistin can reportedly increase alveolar levels of the drug without increasing systemic toxicity. Good clinical results have been obtained in patients with cystic fibrosis, but conflicting data have been reported in patients with VAP. We conducted a retrospective, 1:1 matched case-control study to evaluate the efficacy and safety of AS plus IV colistin vs IV colistin alone in 208 patients in the ICU with VAP caused by COS Acinetobacter baumannii, Pseudomonas aeruginosa, or Klebsiella pneumoniae. Compared with the IV colistin cohort, the AS-IV colistin cohort had a higher clinical cure rate (69.2% vs 54.8%, P = .03) and required fewer days of mechanical ventilation after VAP onset (8 days vs 12 days, P = .001). In the 166 patients with posttreatment cultures, eradication of the causative organism was also more common in the AS-IV colistin group (63.4% vs 50%, P = .08). No between-cohort differences were observed in all-cause ICU mortality, length of ICU stay after VAP onset, or rates of acute kidney injury (AKI) during colistin therapy. Independent predictors of clinical cure were trauma-related ICU admission (P = .01) and combined AS-IV colistin therapy (P = .009). Higher mean Simplified Acute Physiology Score II (P = .002) and Sequential Organ Failure Assessment (P = .05) scores, septic shock (P &lt; .001), and AKI onset during colistin treatment (P = .04) were independently associated with clinical failure. Our results suggest that AS colistin might be a beneficial adjunct to IV colistin in the management of VAP caused by COS GNB.

Colistin use in pediatric intensive care unit for severe nosocomial infections: experience of an university hospital

BackgroundThe aim of this study was to investigate the efficacy and safety of colistin therapy in pediatric patients with severe nosocomial infections in pediatric intensive care unit.MethodsThe medical records of patients treated with colistin at a 200-bed university children hospital were reviewed.ResultThirty-one patients (male/female = 22/9; median age, 3 years; range, 3 months-17 years) received forty-one courses of colistin. The average dose of colistin was 4.9 ± 0.5 mg/kg/day and average treatment duration was 19.8 ± 10.3 days. Three patients who received concomitant nephrotoxic agent with colistin developed nephrotoxicity. Colistin treatment was well tolerated in other patients, and neurotoxicity was not seen in any patient. Favourable outcome was achieved in 28 (68.3%) episodes. Twelve patients died during the colistin therapy. Six of these patients died because of primary underlying disease. The infection-related mortality rate was found 14.6% in this study.ConclusionIn our study, colistin therapy was found to be acceptable treatment option for the severe pediatric nosocomial infections caused by multi-drug resistant bacteria. However, the use of concomitant nephrotoxic drugs with colistin must be avoided and renal function test should be closely monitored.

Biological Cost of Different Mechanisms of Colistin Resistance and Their Impact on Virulence in Acinetobacter baumannii

Two mechanisms of resistance to colistin have been described in Acinetobacter baumannii. One involves complete loss of lipopolysaccharide (LPS), resulting from mutations in lpxA, lpxC, or lpxD, and the second is associated with phosphoethanolamine addition to LPS, mediated through mutations in pmrAB. In order to assess the clinical impacts of both resistance mechanisms, A. baumannii ATCC 19606 and its isogenic derivatives, AL1851 ΔlpxA, AL1852 ΔlpxD, AL1842 ΔlpxC, and ATCC 19606 pmrB, were analyzed for in vitro growth rate, in vitro and in vivo competitive growth, infection of A549 respiratory alveolar epithelial cells, virulence in the Caenorhabditis elegans model, and virulence in a systemic mouse infection model. The in vitro growth rate of the lpx mutants was clearly diminished; furthermore, in vitro and in vivo competitive-growth experiments revealed a reduction in fitness for both mutant types. Infection of A549 cells with ATCC 19606 or the pmrB mutant resulted in greater loss of viability than with lpx mutants. Finally, the lpx mutants were highly attenuated in both the C. elegans and mouse infection models, while the pmrB mutant was attenuated only in the C. elegans model. In summary, while colistin resistance in A. baumannii confers a clear selective advantage in the presence of colistin treatment, it causes a noticeable cost in terms of overall fitness and virulence, with a more striking reduction associated with LPS loss than with phosphoethanolamine addition. Therefore, we hypothesize that colistin resistance mediated by changes in pmrAB will be more likely to arise in clinical settings in patients treated with colistin.

A retrospective study on the effects of colistin therapy in children with multidrug-resistant Gram-negative bacterial pathogens: impact of HIV status on outcome

BackgroundNosocomially acquired multidrug-resistant (MDR) Gram-negative bacteria are important contributors to paediatric intensive care unit (PICU) mortality and morbidity, with limited treatment options.AimTo investigate the outcomes of all children treated with...