Colistin use in critically ill neonates: A case–control study

Accepted Manuscript Colistin use in critically ill neonates: A case-control study Mehmet Sah İpek, MD, Fesih Aktar, MD, Nilufer Okur, MD, Muhittin Celik, MD, Erdal Ozbek, MD PII:

S1875-9572(17)30176-6

DOI:

10.1016/j.pedneo.2016.10.002

Reference:

PEDN 656

To appear in:

Pediatrics & Neonatology

Received Date: 2 May 2016 Revised Date:

27 August 2016

Accepted Date: 6 October 2016

Please cite this article as: İpek MS, Aktar F, Okur N, Celik M, Ozbek E, Colistin use in critically ill neonates: A case-control study, Pediatrics and Neonatology (2017), doi: 10.1016/j.pedneo.2016.10.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title Page Title: Colistin Use in Critically Ill Neonates: A Case-control Study

Corresponding author (the first author)

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Running title: Colistin & Neonate

Hospital, Diyarbakir, Turkey, [email protected],

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Mehmet Sah İpek, MD, Division of Neonatology, Department of Pediatrics, Memorial Dicle

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Memorial Dicle Hospital Urfa Road 3rd km, No:150, Kayapinar, Diyarbakir, Turkey, Tel:+904123156666-1519, Fax:+904123156615 Co-authors (in order)

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Fesih Aktar, MD, Department of Pediatrics, Dicle University Faculty of Medicine, Diyarbakir, Turkey, [email protected]

Nilufer Okur, MD, Department of Pediatrics, Maternity and Children’s Hospital, Diyarbakir,

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Turkey, [email protected]

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Muhittin Celik, MD, Division of Neonatology, Department of Pediatrics, Diyarbakir Children’s Hospital, Diyarbakir, Turkey, [email protected] Erdal Ozbek, MD, Department of Microbiology, Maternity and Children’s Hospital, Diyarbakir, Turkey, [email protected]

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Abstract Background: The aim of this study was to assess the safety and efficacy of colistin use in

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critically ill neonates Methods: This was a case-control study that included newborn infants with proven or suspected nosocomial infections between January 2012 and October 2015, at two centers in Diyarbakir,

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Turkey. The clinical and laboratory characteristics and outcomes of patients who received colistin therapy were reviewed and compared to patients who were treated with antimicrobial agents

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other than colistin during the same period.

Results: Forty-seven cases who received intravenous colistin (colistin group) and 59 control patients (control group) were included. There were no significant differences between the groups regarding outcomes and nephrotoxicity, including acute renal failure. Colistin therapy was

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associated with significantly reduced serum magnesium (1.38 ± 0.39 mg/dL vs. 1.96 ± 0.39 mg/dL, p < 0.001) and hypokalemia (46.8% vs. 25.4%, p = 0.026). The patients who received colistin also had longer hospital stays (43 (32‒70) days vs. 39 (28‒55) days, p = 0.047), a higher

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rate of previous carbapenem exposure (40.4% vs. 11.9%, p = 0.001), and a higher age at the onset of infection (13 (10‒21) days vs. 11 (9‒15) days, p = 0.03).

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Conclusion: This study showed that colistin was both effective and safe for treating neonatal infections caused by multidrug-resistant gram-negative bacteria. However, intravenous colistin use was significantly associated with hypomagnesaemia and hypokalemia. Key Words: colistin; neonate; nosocomial infection; multi-drug resistant; gram-negative bacteria

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1. Introduction The emergence of multi-drug resistant (MDR) gram-negative bacteria (GNB) is a major problem

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that increased patients’ morbidity and mortality.1,2 This is a problem not only in developing countries, but also a growing threat in developed countries.1,3,4 A marked decline in the discovery and development of newer antibiotics to treat infections caused by MDR GNB has become a

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demoralizing challenge for clinicians and microbiologists.5

Colistin (colistimethate sodium), a cyclopeptide antibiotic of the polymyxin class, has been

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reevaluated over the last few decades because of its potent antimicrobial activity against certain MDR GNB.4,6 Studies on the safety and efficacy of intravenous (IV) colistin administration have been performed in burn units, intensive care units, and cancer centers, and on patients without cystic fibrosis.7 A few recent studies have shown the efficacy and safety of IV colistin in children

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and neonates.5,8-13 Because of the concomitant use of other drugs in addition to colistin and coexisting clinical conditions, there is still a vague understanding of the safety and efficacy of colistin.5,8 We therefore conducted this study to assess the safety and efficacy of colistin therapy

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for MDR GNB nosocomial infections in neonates, considering the effects of concomitant medications and the coexistence of clinical conditions.

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2. Methods

2.1. Study Design

This retrospective case-control study included critically ill newborn infants with proven or suspected nosocomial infections caused by MDR GNB and treated with IV colistin between January 2012 and October 2015, at two centers in Diyarbakir, Turkey. Surveillance of the nosocomial infections was performed actively by a physician and nurse. The patients were visited

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daily throughout their period of hospitalization, and their information was recorded on patient follow-up cards by the infection control committee. All hospitalized neonates with proven or suspected nosocomial infections that were treated with IV colistin were evaluated, and those

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treated with IV colistin for at least three days were included in the study. Patients with major congenital anomalies or with previous renal impairment were excluded. A case-control study was organized to identify the possible adverse effects of colistin. For comparison, two groups were

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created: the case-patient group (the colistin group) included patients with proven or suspected sepsis caused by MDR GNB and treated with colistin, while the control-patient group included

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those with proven or suspected sepsis who were treated with antimicrobial agents other than colistin. The Non-Interventional Clinical Ethics Committee of Dicle University Medical Faculty approved the study protocol. 2.2. Data collection

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The medical records of all patients were obtained from hospital files. The recorded study variables included the demographic characteristics (gestational age, mode of delivery, sex, and

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birth weight), medical history (underlying disease, comorbidities), postnatal age, information concerning administration of colistin or other antimicrobial agents (prior or concomitant to

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colistin use), invasive procedures, hospital stays, and laboratory tests. The laboratory tests included microbiological studies (blood, urine, cerebrospinal fluid cultures, and antimicrobial sensitivity), biochemical studies (renal function and serum electrolytes), and hematological values (blood counts and C-reactive protein). For evaluation of the possible side effects of colistin, the creatinine, blood urea nitrogen, magnesium, and potassium values, as well as urine output, before therapy with colistin and after at least three days of colistin, were recorded.8 Other clinical conditions (symptomatic patent ductus arteriosus, asphyxia, surgery, etc.) and agents

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(diuretics, anti-inflammatory drugs, and blood-product transfusions, including red blood cells, fresh frozen plasma, platelets, human albumin, and intravenous human immunoglobulin) that are possibly related to renal injury were evaluated, as well as microbiological clearance and clinical

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outcomes. 2.3. Definitions

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Standard definitions of nosocomial infections and clinical sepsis were used according to the criteria of the Centers for Disease Control and Prevention.14 The diagnosis of sepsis was

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established according to the presence of three or more disorders based on the following criteria: (1) temperature instability (hypothermia, hyperthermia); (2) respiratory issues (grunting, intercostal-subcostal retractions, apnea, tachypnea, cyanosis); (3) cardiovascular disorders (bradycardia, tachycardia, poor perfusion, hypotension); (4) neurological problems (hypotonia, lethargy, seizures); and (5) gastrointestinal problems (feeding intolerance, abdominal

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distension).15 Leukopenia (leukocyte count <5000/mm3), leukocytosis (leukocyte count >22,000/mm3), and a CRP level of >12 mg/L were considered indicators of sepsis.12 A positive

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blood culture was required as a standard to verify cases with proven sepsis. Metabolic acidosis was considered when pH was <7.2 and the plasma bicarbonate value was <15 mEq/L in a

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capillary blood sample. Previous antibiotic exposure was defined as systemic antibiotic use for more than 72 hours in the 30 days before infection onset.16 Multi-drug resistant strains were defined as isolates resistant to representatives of three or more classes of antimicrobial agents.1 All comorbidities of prematurity, including respiratory distress syndrome, intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, and patent ductus arteriosus, were based on the latest updated diagnostic criteria in standard textbooks of neonatology.17 Acute renal failure was defined as diminished urine output (<1.0

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mL/kg/h) and a serum creatinine value of greater than 1.5 mg/dL for at least one day’s duration or one which increased by at least 0.2 to 0.3 mg/dl per day.18 The early case fatality rate was defined

as death by any cause within 30 days of the onset of infection.16 2.4. Microbiological methods

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as death within seven days of the onset of infection, and the overall case fatality rate was defined

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At the first center, the blood culture system used was a Bactec 9240 (Becton Dickinson, USA)®. The Automatized Phoenix culture system was used to identify the microorganisms and their

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antibiotic sensitivities. At the second center, identification and antimicrobial susceptibility testing of GNB was performed with a VITEK 2 automated system (bioMerieux, Marcy l’Etoile, France)® according to the manufacturer’s instructions. Tracheal aspirates, urine, and cerebrospinal fluid specimens were inoculated onto a 5% defibrinated sheep blood agar and an eosin-methylene blue agar plate. The breakpoints for susceptibility were those recommended by

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the Clinical Laboratory Standards Institute.19

2.5. Route of colistin administration and dosage

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A course of IV colistin administration was defined as a period of uninterrupted colistin administration of at least three days. The colistin formulation consisted of 150 mg of colistin base

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equivalent colistimethate sodium (Colimycin; Kocak Farma, Istanbul, Turkey)® per vial (30,000 IU/mg).11 The doses of colistin in this study ranged from 2.5 to 5 mg/kg/d and were given in three doses, infused intravenously in 5 mL normal saline over 30 minutes. The indication for colistin use in neonates with sepsis was based on the following: documentation of MDR GNB growth in the blood culture or empirically during an outbreak of MDR GNB sepsis. 2.6. Statistical analysis

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Statistical analysis was performed using SPSS statistical software (version 17; SPSS, Chicago, IL, USA). The Shapiro-Wilk test was performed to examine the distribution of data. Student’s ttest was used to compare continuous parametric variables, the Mann-Whitney U test was used to

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compare continuous nonparametric variables, and χ2 or Fisher’s exact tests were used for categorical variables when appropriate. A two-tailed P-value of <0.05 was considered to be statistically significant. Parametric continuous variables are expressed as mean ± standard

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and categorical variables are expressed as numbers (%).

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deviation, nonparametric continuous variables are expressed as the median (interquartile range),

3. Results

Of 4,560 patients admitted to two neonatal intensive care units (NICUs) during the study period, 304 (6.6%) developed clinical signs of nosocomial sepsis. Seventy-five neonates received IV

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colistin, and among whom 47 (62.7%) were included in the study, based on the inclusion criteria. The remaining 229 patients with nosocomial sepsis were evaluated as control patients, and of these, 59 (25.8%) met the inclusion criteria. Sepsis was confirmed in 42 (89.4%) and 44 (74.6%)

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infants in the colistin and control groups, respectively (Figure 1). There were no statistically significant differences between the groups regarding baseline

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characteristics, demographic data, and outcomes except for the length of hospital stay, which was longer in the colistin group, as well as the rate of previous carbapenem exposure within one month before infection, which was higher in the colistin group (Table 1). There were no statistically significant differences between the groups regarding serum levels of blood urea nitrogen, creatinine, potassium, and magnesium before treatment (p > 0.05). The clinical and laboratory characteristics of the groups during the infection are listed in Table 2. The colistin group was older at the onset of infection, compared to the control group (p < 0.05). During the

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treatment of infection, serum magnesium levels were lower and hypokalemia rates were higher in the colistin group compared to the control group (p < 0.001 and p < 0.05, respectively). Magnesium levels were significantly lower during the colistin therapy compared to the beginning

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of treatment (2.10 ± 0.29 vs. 1.38 ± 0.39 mg/dL, respectively; p < 0.001). The need for additional magnesium supplementation during the infection was significantly higher in the colistin group than the control group (69.5% vs. 10.5%, respectively; p < 0.001).

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All patients in the colistin group received IV colistin therapy. Concomitant use of the IV route,

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colistin was given intraventricularly in three patients with meningitis and ventriculoperitoneal shunts, and by inhalation in four patients with ventilator-associated pneumonia. The mean duration of colistin administration was 18 ± 7.9 days. Colistin was administered concomitantly with at least one other antimicrobial agent in all patients. Five patients received colistin empirically without a positive culture but with signs of systemic infection during a hospital

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outbreak of Acinetobacter baumannii. Additionally, two patients who received colistin empirically during outbreak had the growth of Serratia marcescens in blood culture, but colistin administration was continued until the second result. The clinical improvement in these patients

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was achieved by other antibiotics concomitantly used, because of Serratia marcescens was

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resistant to colistin. In the colistin group, among 40 culture-positive patients, four (10%) did not show microbiological clearance of Acinetobacter baumannii, based on subsequent culture positivity. Of these patients, two had meningitis (with hydrocephalus and ventriculoperitoneal shunts), and the remaining two had severe pneumonia and previous abdominal surgeries. All of these patients died after between 10 and 28 days of treatment. The persistence of culture positivity was not detected in the control group.

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The isolated microorganisms and sources of isolation according to the group are shown in Table 3. Antimicrobial sensitivity of isolates in the colistin group was as follows: a) isolates of Acinetobacter baumannii (n = 34) were resistant to all antibiotics including penicillins (97%),

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aminoglycosides (97%), carbapenems ( 94%), and fluorquinolones (97%), and were sensitive to colistin (100%) and trimethoprim/sulfamethoxazole (97%); b) isolates of Klebsiella pneumoniae (n = 6) were resistant to all antibiotics including penicillins (100%), aminoglycosides (67%),

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carbapenems ( 100%), and fluorquinolones (100%), and were sensitive to colistin (100%) and tigecycline (100%); c) both isolates of Serratia marcescens were sensitive to aminoglycosides

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and carbapenems, and were resistant to penicillins, cephalosporins and colistin.

4. Discussion

In this case-control study, we evaluated the adverse effects and efficacy of IV colistin

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administration in critically ill neonates for the treatment of infections due to MDR GNB. It was found that the use of colistin in critically ill neonates was not associated with significant adverse effects, similar to recent studies.8-13 However, serum magnesium and potassium levels need close

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monitoring during the colistin therapy. Following the revival of the use of colistin in the last decade, a limited number of case series evaluating colistin use in neonates have been

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published,5,8,10-13 but there have been no previous case-control or prospective studies. There were two significant differences among the baseline features of the two groups in this study. First, previous carbapenem administration was significantly higher in the colistin group. This finding is not surprising, as previous carbapenem exposure has been described as significantly related to the development of multi-drug bacterial resistance.1,16 The second significant difference was the length of NICU stay (correlating with age at onset of infection), which has been reported as a risk factor for the development of resistance.1,20

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In the present study, all patients receiving colistin therapy had serious infections with MDR GNB, all of which were resistant to carbapenem. Nevertheless, all patients in the colistin group received at least one additional antibiotic, most commonly meropenem or amikacin, despite

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documented resistance. The use of additional antibiotics concomitant with colistin has also been reported in previous studies.5-13 This approach is based on the fact that carbapenems, rifampicin, and/or aminoglycosides can show synergistic activity with colistin.4,21 It is suggested that the

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combination of colistin with other antibiotics can minimize the potential for emergence of resistance with colistin monotherapy against Acinetobacter baumannii.6 However, this issue

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needs prospective investigations to determine the rational combinations.

Nephrotoxicity is one of the major concerns associated with colistin use; its rate has been reported at up to 30% in recent studies.6-8,22 In a systemic review conducted by Falagas et al on IV colistin use in pediatric patients, it was reported that hematuria, proteinuria, cylindruria, and

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renal tubular cells in the urine ranged from 1% to 10%.7 Jajoo et al reported that renal impairment developed in two of 18 preterm newborns in their case series.5 Similarly, in another case series, Alan et al reported a renal impairment rate of 19%, with none of the surviving patients requiring

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renal replacement therapy.8 They also determined that a significant number of patients on colistin

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therapy needed additional electrolyte supplementation, such as magnesium and potassium.8 In our study, colistin therapy was significantly related with decline in serum potassium and magnesium levels, but there was no significant association between renal impairment and colistin therapy. Little information is available on the mechanisms inducing nephrotoxic events. An experimental study showed that colistin was directly toxic to mammalian urothelium by increasing transepithelial conductance.23 The electrolyte deficiency during colistin therapy may be explained by the renal tubulopathy resulting from the same toxic mechanism.

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Because severe sepsis is usually associated with organ dysfunction, it has been suggested that assessment of the contribution of colistin to renal impairment may be difficult.5 Additionally, this circumstance can be more complicated with clinical comorbidities and other concomitant

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nephrotoxic medications.4 Considering the conditions potentially related to renal injury, the present study showed that colistin did not significantly influence renal function in critically ill neonates. It is important to note that acute renal failure occurs in as many as 8% of neonates

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admitted to NICUs,18,25 and this rate is higher in neonates with sepsis.26 Therefore, it is not

such as amikacin or amphotericin B.

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unreasonable to state that nephrotoxicity of colistin is not greater than that of other medications,

In this study, the dosing of colistin was comparable to the average of doses used in previous reports (ranging from 40,000 to 300,000 IU/kg/d).5,8-13 The administration of these doses may be a reason for the low observed incidence of nephrotoxicity when compared to previous

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studies.7,24,27 However, urinary analyses could not be evaluated because the retrospective nature of the study did not allow access to adequate data. Renal injury can also be caused by prolonged use of colistin, as well as high doses.4,6,27 However, there are limited data on the safety of

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prolonged colistin therapy in neonates. A case of Bartter-like syndrome developing after 26 days of colistin therapy has been reported,8 whereas important adverse effects might not be seen in

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another patient receiving colistin for more than three months.10 It is suggested that nephrotoxicity is not associated with the dose per day, but rather with the total cumulative dose.27 In conclusion, renal injury caused by colistin is relatively mild and usually reversible after cessation of therapy, but it should be closely monitored.6,8,27 Another adverse effect of the IV administration of colistin is neurotoxicity, which is rare.4 Among neurological findings, only apnea and convulsion are clinically recognizable in neonates.8

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Thus far, small numbers of studies on neonates have not reported any evident neurotoxicity related to colistin use.5,8,10,12,13 Although there were various coexisting clinical conditions, which may be similar to neurotoxic findings, no adverse neurological events attributable to colistin were

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noted in the present study. Prospective studies are needed to explore the effect of colistin on the neonatal brain. Amplitude-integrated electroencephalography may be a useful tool to define brain activity during the administration of colistin.

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In this study, there was no significant difference between the groups regarding outcomes, despite

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the colistin group including MDR GNB infections. On the contrary, the early case fatality rate seemed lower in the colistin group. This probably resulted from the inclusion criteria, which allowed patients who had received colistin for more than 72 hours to be included in the study. Thus, 10 patients who died within 72 hours of treatment were excluded from the analysis. The early demise of these patients was probably the result of inappropriate empirical antibiotic

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therapy or a delay in appropriate antibiotics.

Microbiological clearance could not be achieved in four patients of the colistin group, in whom

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bacteria were isolated from the cerebral ventricles (two patients), the respiratory tract (one patient), and the blood (one patient with peritonitis). The presence of a foreign device and

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inadequate penetration into the site of infection may have played a role in the failure of clearance in these patients.7,10 Concerns about inadequate penetration via the IV route has led to the use of various routes for the administration of colistin, and most published studies have reported good results.2,28-30 The overall case fatality rate in the colistin group was comparable to previous case series on neonates,5,8-13 but it was not significantly different between the two groups in our study. Moreover, some recent studies using lower colistin dosages reported similar survival rates,5,8,10 which contradict concern that low dosage use of colistin might lead to emergence of resistance.11

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We suggest that the clinical use of colistin is as effective as other antibiotics commonly used in neonates.

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Although this study included a control group and minimized the effects of concomitant medications and coexisting clinical conditions, there were still some limitations. First, given the retrospective nature of the study, the data may not have included some necessary variables (such as illness severity score). Second, a molecular epidemiologic analysis of MDR microorganism

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types could not be performed due to the limitations of the facilities. Third, because the study was

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conducted at two centers, there was a potential for diversity of clinical practices between the centers. Finally, the fact that neurological toxicity was difficult to evaluate properly, due to critical illnesses and prematurity, requires a novel approach for undetectable effects. Studies with larger numbers of patients and more comprehensive analyses can provide further data on these variables and limitations.

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In conclusion, this case-control study also supported that the use of IV colistin (colistimethate sodium) in neonates was not associated with significant adverse effects that require

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discontinuation. However, serum magnesium and potassium levels should be closely monitored during colistin therapy. Although it seems that the efficacy of colistin is satisfactory for favorable

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outcomes, it should be kept in mind that colistin is an important last-line antibiotic for the treatment of MDR GNB infections.

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Conflict of Interest The authors declare that they have no conflict of interest.

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24. Falagas ME, Rafailidis PI, Ioannidou E, Alexiou VG, Matthaiou DK, Karageorgopoulos DE, et al. Colistin therapy for microbiologically documented multidrug-resistant Gramnegative bacterial infections: a retrospective cohort study of 258 patients. Int J Antimicrob Agents 2010;35:194‒9.

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26. Mathur NB, Agarwal HS, Maria A. Acute renal failure in neonatal sepsis. Indian J Pediatr 2006; 73:499‒502. 27. Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, et al. Nephrotoxicity

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Table 1 Demographic data, baseline characteristics, and outcomes.

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19

Colistin Group

Control Group

(n = 47)

(n = 59)

Gestational age (weeks)

32.1 ± 4.2

Birth weight (g)

1724 ± 704

Male gender

23 (48.9%)

Cesarean section delivery

31.6 ± 3.4

P Value

0.543 0.268

32 (54.2%)

0.696

28 (59.6%)

41 (69.5%)

0.311

Antenatal steroids

10 (21.3%)

15 (24.5%)

0.65

APGAR score at 5 minutes (≤7)

21 (44.7%)

20 (33.9%)

0.317

5 (10.6%)

4 (6.8%)

0.506

23 (48.9%)

27 (45.7%)

0.845

10 (21.3%)

14 (23.7%)

0.819

Short-term morbidity Perinatal asphyxia Hyaline membrane disease Patent ductus arteriosus Intraventricular hemorrhage (grade III and IV) Cholestasis

Bronchopulmonary dysplasia Retinopathy of prematurity Previous surgery (within 1 month) Previous antibiotic exposure† Third-generation cephalosporin

EP

Carbapenem

TE D

Necrotizing enterocolitis

Invasive mechanical ventilation

M AN U

SC

1587 ± 503

‡

14 (29.8%)

9 (15.3%)

0.097

9 (19.1%)

7 (11.9%)

0.414

8 (17%)

10 (16.9%)

>0.99

14 (29.8%)

10 (16.9%)

0.161

7 (14.9%)

3 (5.1%)

0.104

5 (10.6%)

2 (3.4%)

0.237

7 (14.9%)

8 (13.6%)

>0.99

19 (40.4%)

7 (11.9%)

0.001

21 (44.7%)

28 (47.5%)

0.846

37 (78.7%)

43 (72.9%)

0.507

19 (40.4%)

20 (33.9%)

0.546

43 (32-70)

39 (28-55)

0.047

1 (2.1%)

4 (6.8%)

0.379

Overall case fatality

10 (21.3%)

8 (13.6%)

0.311

Discharged alive

33 (70.2%)

48 (81.4%)

0.250

Total parenteral nutrition‡

AC C

Central venous catheter‡

Length of hospital stay (days) Outcome

Early case fatality

Data are expressed as mean ± SD, median (interquartile range), or number (%). †

Within 1 month before onset of infection

‡

Within 1 week before onset of infection

ACCEPTED MANUSCRIPT 20

Table 2 Clinical and laboratory characteristics of patients during infection. Colistin Group (n = 47) 13 (10‒21)

RI PT

Age at onset of infection (days)

Control Group (n = 59) 11 (9‒15)

P Value 0.03

42 (89.4%)

44 (74.6%)

0.79

Blood product transfusion

31 (65.9%)

41 (69.5%)

0.834

Metabolic acidosis

14 (29.7%)

14 (23.7%)

0.513

Invasive mechanical ventilation (>2 days)

23 (48.9%)

23 (38.9%)

0.33

Total parenteral nutrition (>5 days)

33 (70.2%)

43 (72.9%)

>0.99

133 (76‒191)

88 (50‒175)

0.124

30 (63.4%)

45 (76.3%)

0.199

21 (44.7%)

27 (45.7%)

>0.99

23 (48.9%)

25 (42.4%)

0.558

45 (95.7%)

56 (94.9%)

>0.99

31 (65.9%)

44 (74.6%)

0.392

8 (17%)

10 (16.9%)

>0.99

9 (19.1%)

16 (27.1%)

0.367

Thrombocytopenia (<100×103/mm3)

27 (57.4%)

31 (52.5%)

0.696

Blood urea nitrogen (mg/dL)

30 (16‒52)

25 (12‒35)

0.101

0.6 (0.4‒0.7)

0.6 (0.4‒0.8)

0.169

Potassium (<3.5 mEq/L)

22 (46.8%)

15 (25.4%)

0.026

Magnesium (mg/dL)

1.38 ± 0.39

1.96 ± 0.39

<0.001

Urinary output (<1 ml/kg/h)

16 (34%)

13 (22%)

0.193

Acute renal failure

6 (12.8%)

8 (13.6%)

>0.99

SC

Positivity of blood culture

CRP at onset of infection (mg/dL)

Respiratory stimulants (caffeine or aminophylline) Inotropes (dopamine or dobutamine) Diuretics (>3 doses) Meropenem Amikacin

Metronidazole Laboratory

AC C

EP

Creatinine (mg/dL)

TE D

Amphotericin B

M AN U

Concomitant medications

Data are expressed as mean ± SD, median (interquartile range), or number (%). CRP, C-reactive protein

ACCEPTED MANUSCRIPT 21

Source of Isolation Colistin Group (n = 42)

Klebsiella pneumoniae

Blood (n = 6)

Serratia marcescens

Blood (n = 2)‡

Control Group (n = 44)

SC

Blood (n = 26), TA (n = 6), CSF (n = 4)†

Acinetobacter baumannii

RI PT

Table 3 Distribution and source of isolated microorganisms.

Blood (n = 26), CSF (n = 2)†

Klebsiella pneumoniae

Blood (n = 8)

Serratia marcescens

Blood (n = 3)

M AN U

Escherichia coli

Pseudomonas aeruginosa

Blood (n = 3)

Staphylococcus aureus

Blood (n = 2)

Candida spp.

Blood (n = 2)

†

Two patients also had positive blood cultures. Serratia marcescens is colistin-resistant. Colistin use was empirically started and continued due to hospital outbreak of Acinetobacter baumannii sepsis until the documentation of the negative cultures. TA, tracheal aspirate; CSF, cerebrospinal fluid

AC C

EP

TE D

‡

ACCEPTED MANUSCRIPT 22

Figure legends Flow chart of the study.

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT