health care - associated infections ( hcai ) lead to mortality and morbidity in neonatal intensive care units ( nicu ) . the frequency of hcai in the nicu were reported to range between 7% and 24% . in the last 2 decades there has been a rapid increase in resistance to infections caused by multidrug - resistant gram - negative bacilli ( mdr - gnb ) , especially pseudomonas aeruginosa , acinetobacter baumannii , and klebsiella pneumonia . since the production of antibiotics that can treat mdr - gnb infections is limited , the use of colistin has increased worldwide . in previous years , the parenteral use of colistin has been reported to have many toxic effects , including nephrotoxicity , and although studies in recent years showed that toxic adverse effects might not be as common as previously thought , the use of colistin is limited to mdr - gnb infections that have clinical and microbiological resistance . in addition , there is very little data regarding the effectiveness and safety of intravenous ( iv ) colistin use in newborns . in this study we aimed to investigate the efficacy and safety of colistin use in mdr - gnb infections that occur in the neonatal period . the files of newborn patients infected with mdr - gnb and treated with colistin were evaluated retrospectively . patients whose diagnostic culture tests confirmed the mdr infection and who were treated with colistin for at least 72 h between january 2013 and june 2015 were included in the study . we recorded demographic data , underlying diseases , hospitalization time in the nicu , ventilator care , surgical procedures , isolated microorganism , location of isolation , antibiotic sensitivity , colistin dose and duration , baseline serum creatinine , level of creatinine during and after colistin treatment , use of other nephrotoxic antibiotics and/or medications , and clinical and microbiological course . the diagnosis of infection was made based on the clinical findings and isolation of bacteria from sterile body sites outlined in the centers for disease control and prevention ( cdc ) guideline . the mdr was considered as a gram - negative microorganisms resistant to at least 3 different antibiotic groups . clinical response was accepted as resolution of initial symptoms and signs , tolerance to oral feeding , and weight gain . clinical unresponsiveness was considered as continuation or worsening of the initial signs and symptoms , development of new infection , or radiological deterioration . patients that were lost were further evaluated to investigate whether their cause of death was infection . renal impairment was considered as an at least 0.5 mg / dl increase in serum creatinine compared to basal levels at any time after 24 h had passed since colistin treatment was initiated or 2-fold increase of serum creatinine levels compared to baseline levels . cultures were taken from patients with suspected infection at the beginning and throughout the treatment : venous blood , central venous catheter ( cvc ) , endotracheal aspirate ( eta ) , cerebrospinal fluid ( csf ) , and urine . blood culture samples were seeded into bactec peds plus / f ( bd , sparks , md ) culture flasks . all microbiological samples were inoculated into routine culture media ( macconkey agar , blood agar , and chocolate agar ) . the identification of microorganisms was done by biochemical tests and the vitek-2 compact system . the antimicrobial susceptibility to colistin was tested by e - test based on the clinical laboratory standards institute ( clsi ) guideline . among the isolated bacteria , the ones that had the minimum inhibitory concentration ( mic ) of 2 mg / dl were considered to be sensitive to colistin . the colistin treatment was initiated in patients that did not have any other options based on their culture results . the empirical colistin treatment was initiated based on the clinical surveillance data and/or in patients not responsive to other broad - spectrum antibiotics . however , the study only included patients who were identified to have mdrgnb based on their culture results . patients were administered a commercial formulation that contained 150 mg of colistin in each vial . all patients received standard colistin treatment of 5 mg / kg / day given in 3 doses as infusion in 5 ml saline for at least 30 min . patients were evaluated for clinical and microbiological response , as well as for adverse effects of colistin . all patients were followed - up for 10 days after the end of treatment in order to monitor for nephrotoxicity . control cultures were obtained from all patients 4896 h after the initiation of colistin treatment . parents of all patients were informed about the treatment and verbal consent was obtained from all of them prior to the treatment . the spss 18.0 for windows ( spss , chicago , il ) program was used for statistical analysis . the shapiro - wilk test was used to determine whether the variables followed normal distribution . the variables that followed normal distribution are expressed as mean ( sd ) and the ones that did not follow normal distribution are expressed as median ( min  max ) and frequency ( n,% ) . the spss 18.0 for windows ( spss , chicago , il ) program was used for statistical analysis . the shapiro - wilk test was used to determine whether the variables followed normal distribution . the variables that followed normal distribution are expressed as mean ( sd ) and the ones that did not follow normal distribution are expressed as median ( min  max ) and frequency ( n,% ) . none of the patients received 2 or more courses of colistin treatment . the demographic data and admission diagnosis and health care - associated infections ( hais ) the presence of bacteria was shown with cultures from at least 1 site in all patients . several antimicrobials had been used prior to or with colistin ( table 3 ) . in our study , 20% of the microorganisms were sensitive to amikacin , 4.6% to ciprofloxacin , and 4.6% were sensitive to both ciprofloxacin and amikacin . while the mortality with microorganisms that are only sensitive to colistin was 21.7% , the mortality related to infections by microorganisms that were sensitive to amikacin and/or ciprofloxacin was 21% . moreover , nephrotoxic drugs such as ibuprofen were used in 6 patients ( 9.2% ) and contrast agents in 3 patients ( 4.6% ) . while complete clinical remission was achieved in 51 patients ( 78.5 ) , 14 patients ( 21.5% ) died during the treatment . four patients ( 6.2% ) died due to another infection and none of these patients developed colistin toxicity ( table 4 ) . nephrotoxicity was observed in 3 patients , but clinical improvement was achieved in all 3 . convulsions appeared in 3 patients and apnea developed in 1 patient . while 1 of the patients that developed convulsions had hie , the other 2 had no organic pathology to explain the cause of seizures ( table 5 ) . two patients developed rash , but their rashes recovered spontaneously without any need to interrupt the treatment . colistin is a cationic polypeptide antibiotic belonging to the polymyxin family , that kills bacteria by disrupting cellular functions . parenteral colistin use in newborns was first reported in 1970 . however , at that time colistin was administered via intramuscular routes and in high doses , leading to high rates of toxicity . lately , the use of colistin in mdr infections has increased due to increasing resistance to gnb . however , there is not enough data about use and dosage of colistin in newborns . the success rate of colistin in mdr - gnb infections in pediatric treatment studies has been reported to vary between 70% and 87.5% . all of our patients were administered the standard 5 mg / kg / day in 3 doses . none of the patients required intrathecal or intraventricular treatment . long - term use and reaching high tissue concentrations , especially while treating infections such as ventriculitis and pneumonia , may lead to development of resistance to colistin . in our study , similar results have been reported in recent studies performed with pediatric patients [ 6,1315 ] . the data on the efficacy and safety of colistin are insufficient and there are almost no data regarding the use of colistin in the neonatal period . it was reported that pediatric patients were treated with colistin for 40 , 42 , 46 , 51 , 70 , and 93 days , 1 patient received an iv colistin treatment for 133 days , and this long - term use of colistin did not lead to development of toxicity . in an experimental study , animals were given high - dose ( 1224 mg / kg / day ) colistin for 15 days and none of the animals developed nephrotoxicity . in our study , the longest colistin treatment was for 24 days with a dose of 5 mg / kg / day and no toxicity was observed in this patient . before 1980 , this reduction in nephrotoxicity can be explained by the use of less toxic colistimethate sodium , better patient monitoring in the icu , and avoiding the simultaneous use of nephrotoxic drugs . studies have shown that use of antibiotics other than colistin may lead to higher rates of nephrotoxicity compared to that of colistin . moreover , colistin has been reported to be less nephrotoxic than tobramycin or amikacin . in our study , it is noteworthy that 29% of the patients were treated with aminoglycosides prior to or with colistin and none of them developed nephrotoxicity . in some cases , nephrotoxic effects of colistin colistin - associated nephrotoxicity mostly occurs within the first 5 days to a week and patients that develop nephrotoxicity have higher mortality rates [ 2123 ] . however , its progression is often mild and is improved when the use of colistin is discontinued [ 1,3,2426 ] . although the population in our study was very sensitive , the nephrotoxicity developed after the 10 day , and consistent with the literature , improved rapidly when colistin was discontinued . neurotoxicity was often observed when colistin was first introduced , but studies conducted in recent years showed very little or no colistin - associated neurotoxicity . . it may lead to weakness , facial and peripheral paresthesia , ophthalmoplegia , dysphagia , ataxia , ptosis , partial deafness , vision disorders , vertigo , confusion , hallucinations , seizures , and neuromuscular blockade . in our study , convulsions were seen in 3 patients . however , 1 of these patients had hypoxia sequels , as well as other neurological problems therefore , we believe that apnea was associated with the primary disease ( table 5 ) . despite these 4 patients , the neurotoxicity rate was not very high . although the low rate of neurotoxicity could be due to low levels of colistin - associated neurotoxicity , it might also be because the study was conducted retrospectively , most of the patients were premature infants , and because patients had received sedoanalgesia . the sensitivity of active microorganisms to the second antibiotic may affect the clinical and microbiological response . however , in our study there was no difference between the group that was sensitive to colistin alone and the group that was sensitive to a second antibiotic in terms of mortality and microbiological response . the retrospective design and lack of a control group are limits of our study . prematurity , other treatments , and sedoanalgesics received by the patients made it difficult to assess adverse effects , especially neurological ones . moreover , some patients were receiving medications in addition to colistin , which made it impossible to evaluate the effects of colistin alone . furthermore , patients received other nephrotoxic drugs , thus it was not fully understood how much of the toxicity was due to colistin . we believe that given the severity and mortality of the disease , the adverse effects of colistin are acceptable . we found that colistin is highly effective and safe in treating infections caused by mdr - gnb .
backgroundthe emergence of infections related to multidrug - resistant gram - negative bacilli ( mdr - gnb ) reintroduced the use of colistin , an antibiotic that was previously abandoned due to adverse effects . 
 however , because of its limited use in neonatal intensive care units , there is very little data about the effectiveness and safety of colistin in children and newborns . in this study , which will be the largest case study in the literature 
 , we aimed to evaluate the effectiveness and safety of colistin in full - term and preterm newborns.material/methodsthe study included patients admitted into 2 level 3 neonatal intensive care units between january 2013 and june 2015 . 
 the medical records of patients diagnosed with sepsis , meningitis , pneumonia , and urinary tract infection based on the diagnostic culture results and treated with colistin were analyzed retrospectively . 
 the patients whose infections were not verified were excluded from the study.resultsthe study included 65 patients ( 18 term , 47 preterm ) . 
 the most frequently isolated pathogens were klebsiella pneumoniae and acinetobacter baumannii followed by pseudomonas aeruginosa and enterobacter cloacae . 
 mean colistin treatment time was 153.5 days . 
 all patients treated with colistin were being treated with at least 1 other antibiotic . 
 while a complete clinical response was achieved in 51 ( 72.3% ) patients , 14 ( 21.5% ) patients died during treatment . 
 four ( 7.7% ) patients died during as a result of another infection . 
 three patients developed renal toxicity , another 3 patients had seizures , and apnea was observed in 3 patients.conclusionscolistin was found to be effective and safe for treatment of mdr - gnb infections in preterms and infants with very low birth weight . 
 given the severity of the infection , the adverse effects of colistin were at acceptable levels .