Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime

Jens Ulrik Stæhr Jensen; Lars Hein; Bettina Lundgren; Morten H Bestle; Thomas Mohr; Mads H Andersen; Jesper Løken; Hamid Tousi; Peter Søe-Jensen; Anne Øberg Lauritsen; Ditte Strange; John A Petersen; Katrin Thormar; Kim M Larsen; Niels Erik Drenck; Jannik Helweg-Larsen; Maria E Johansen; Kristian Reinholdt; Jens K Møller; Bente Olesen; Maiken C Arendrup; Christian Østergaard; Alessandro Cozzi-Lepri; Jesper Grarup; Jens D Lundgren; Procalcitonin and Survival Study Group

doi:10.1097/CCM.0000000000000746

Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime

Jens Ulrik Stæhr Jensen, Lars Hein, Bettina Lundgren, Morten H Bestle, Thomas Mohr, Mads H Andersen, Jesper Løken, Hamid Tousi, Peter Søe-Jensen, Anne Øberg Lauritsen, Ditte Strange, John A Petersen, Katrin Thormar, Kim M Larsen, Niels Erik Drenck, Jannik Helweg-Larsen, Maria E Johansen, Kristian Reinholdt, Jens K Møller, Bente OlesenMaiken C Arendrup, Christian Østergaard, Alessandro Cozzi-Lepri, Jesper Grarup, Jens D Lundgren, Procalcitonin and Survival Study Group

23 Citations (Scopus)

Abstract

OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.

DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.

SETTING: Nine multidisciplinary ICUs across Denmark.

PATIENTS: A total of 1,200 critically ill patients.

INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).

MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).

CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.

Original language	English
Journal	Critical Care Medicine
Volume	43
Issue number	3
Pages (from-to)	594-602
Number of pages	9
ISSN	0090-3493
DOIs	https://doi.org/10.1097/CCM.0000000000000746
Publication status	Published - 4 Mar 2015

Keywords

APACHE
Age Factors
Aged
Anti-Bacterial Agents
Candidiasis, Invasive
Cefuroxime
Ciprofloxacin
Critical Illness
Denmark
Dose-Response Relationship, Drug
Drug Administration Schedule
Female
Humans
Intensive Care Units
Male
Middle Aged
Penicillanic Acid
Piperacillin
Single-Blind Method
Thienamycins

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Jensen, J. U. S., Hein, L., Lundgren, B., Bestle, M. H., Mohr, T., Andersen, M. H., Løken, J., Tousi, H., Søe-Jensen, P., Lauritsen, A. Ø., Strange, D., Petersen, J. A., Thormar, K., Larsen, K. M., Drenck, N. E., Helweg-Larsen, J., Johansen, M. E., Reinholdt, K., Møller, J. K., ... Procalcitonin and Survival Study Group (2015). Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime. Critical Care Medicine, 43(3), 594-602. https://doi.org/10.1097/CCM.0000000000000746

Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients : Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime. / Jensen, Jens Ulrik Stæhr; Hein, Lars; Lundgren, Bettina et al.

In: Critical Care Medicine, Vol. 43, No. 3, 04.03.2015, p. 594-602.

Research output: Contribution to journal › Journal article › Research › peer-review

Jensen, JUS, Hein, L, Lundgren, B, Bestle, MH, Mohr, T, Andersen, MH, Løken, J, Tousi, H, Søe-Jensen, P, Lauritsen, AØ, Strange, D, Petersen, JA, Thormar, K, Larsen, KM, Drenck, NE, Helweg-Larsen, J, Johansen, ME, Reinholdt, K, Møller, JK, Olesen, B, Arendrup, MC, Østergaard, C, Cozzi-Lepri, A, Grarup, J, Lundgren, JD & Procalcitonin and Survival Study Group 2015, 'Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime', Critical Care Medicine, vol. 43, no. 3, pp. 594-602. https://doi.org/10.1097/CCM.0000000000000746

Jensen JUS, Hein L, Lundgren B, Bestle MH, Mohr T, Andersen MH et al. Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime. Critical Care Medicine. 2015 Mar 4;43(3):594-602. doi: 10.1097/CCM.0000000000000746

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title = "Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients: Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime",

abstract = "OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.SETTING: Nine multidisciplinary ICUs across Denmark.PATIENTS: A total of 1,200 critically ill patients.INTERVENTION: Patients were randomly allocated to either a {"}high exposure{"} antibiotic therapy (intervention arm, n = 604) or a {"}standard exposure{"} guided by current guidelines (n = 596).MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, {"}invasive Candida infection,{"} 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.",

keywords = "APACHE, Age Factors, Aged, Anti-Bacterial Agents, Candidiasis, Invasive, Cefuroxime, Ciprofloxacin, Critical Illness, Denmark, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Intensive Care Units, Male, Middle Aged, Penicillanic Acid, Piperacillin, Single-Blind Method, Thienamycins",

author = "Jensen, {Jens Ulrik St{\ae}hr} and Lars Hein and Bettina Lundgren and Bestle, {Morten H} and Thomas Mohr and Andersen, {Mads H} and Jesper L{\o}ken and Hamid Tousi and Peter S{\o}e-Jensen and Lauritsen, {Anne {\O}berg} and Ditte Strange and Petersen, {John A} and Katrin Thormar and Larsen, {Kim M} and Drenck, {Niels Erik} and Jannik Helweg-Larsen and Johansen, {Maria E} and Kristian Reinholdt and M{\o}ller, {Jens K} and Bente Olesen and Arendrup, {Maiken C} and Christian {\O}stergaard and Alessandro Cozzi-Lepri and Jesper Grarup and Lundgren, {Jens D} and {Procalcitonin and Survival Study Group}",

year = "2015",

month = mar,

day = "4",

doi = "10.1097/CCM.0000000000000746",

language = "English",

volume = "43",

pages = "594--602",

journal = "Critical Care Medicine",

issn = "0090-3493",

publisher = "Lippincott Williams & Wilkins",

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TY - JOUR

T1 - Invasive Candida Infections and the Harm From Antibacterial Drugs in Critically Ill Patients

T2 - Data From a Randomized, Controlled Trial to Determine the Role of Ciprofloxacin, Piperacillin-Tazobactam, Meropenem, and Cefuroxime

AU - Jensen, Jens Ulrik Stæhr

AU - Hein, Lars

AU - Lundgren, Bettina

AU - Bestle, Morten H

AU - Mohr, Thomas

AU - Andersen, Mads H

AU - Løken, Jesper

AU - Tousi, Hamid

AU - Søe-Jensen, Peter

AU - Lauritsen, Anne Øberg

AU - Strange, Ditte

AU - Petersen, John A

AU - Thormar, Katrin

AU - Larsen, Kim M

AU - Drenck, Niels Erik

AU - Helweg-Larsen, Jannik

AU - Johansen, Maria E

AU - Reinholdt, Kristian

AU - Møller, Jens K

AU - Olesen, Bente

AU - Arendrup, Maiken C

AU - Østergaard, Christian

AU - Cozzi-Lepri, Alessandro

AU - Grarup, Jesper

AU - Lundgren, Jens D

AU - Procalcitonin and Survival Study Group

PY - 2015/3/4

Y1 - 2015/3/4

N2 - OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.SETTING: Nine multidisciplinary ICUs across Denmark.PATIENTS: A total of 1,200 critically ill patients.INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.

AB - OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection.DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.SETTING: Nine multidisciplinary ICUs across Denmark.PATIENTS: A total of 1,200 critically ill patients.INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596).MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006).CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.

KW - APACHE

KW - Age Factors

KW - Aged

KW - Anti-Bacterial Agents

KW - Candidiasis, Invasive

KW - Cefuroxime

KW - Ciprofloxacin

KW - Critical Illness

KW - Denmark

KW - Dose-Response Relationship, Drug

KW - Drug Administration Schedule

KW - Female

KW - Humans

KW - Intensive Care Units

KW - Male

KW - Middle Aged

KW - Penicillanic Acid

KW - Piperacillin

KW - Single-Blind Method

KW - Thienamycins

U2 - 10.1097/CCM.0000000000000746

DO - 10.1097/CCM.0000000000000746

M3 - Journal article

C2 - 25493970

SN - 0090-3493

VL - 43

SP - 594

EP - 602

JO - Critical Care Medicine

JF - Critical Care Medicine

IS - 3

ER -