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.
  
  
  METHODS
  Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010.
  
  
  METHODS
  Nine multidisciplinary ICUs across Denmark.
  
  
  METHODS
  A total of 1,200 critically ill patients.
  
  
  METHODS
  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).
  
  
  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.
authors.affiliation: 1CHIP, Department of Infectious Diseases and Rheumatology, Rigshospitalet - and the University of Copenhagen, Copenhagen, Denmark. 2Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark. 3Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hillerød, Denmark. 4Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Glostrup, Denmark. 5Diagnostic Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. 6Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Gentofte, Denmark. 7Department of Anesthesia and Intensive Care, Aarhus University Hospital, Skejby, Denmark. 8Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Hvidovre, Denmark. 9Department of Anesthesia and Intensive Care, Copenhagen University Hospital, Herlev, Denmark. 10Department of Anesthesia and Intensive Care, Aarhus University Hospital, Aarhus, Denmark. 11Department of Anesthesia and Intensive Care, Roskilde University Hospital, Roskilde, Denmark. 12Department of Clinical Microbiology, Vejle Hospital, University of Southern Denmark, Vejle, Denmark. 13Department of Clinical Microbiology, Copenhagen University Hospital, Hillerød, Denmark. 14Mycology Unit, Statens Serum Institut, Copenhagen, Denmark. 15Department of Clinical Microbiology, Copenhagen University Hospital, Herlev, Denmark. 16Royal Free University College, London, United Kingdom.
authors.forename: Jens-Ulrik S
authors.initials: JU
authors.lastname: Jensen
authors.forename: Lars
authors.initials: L
authors.lastname: Hein
authors.forename: Bettina
authors.initials: B
authors.lastname: Lundgren
authors.forename: Morten H
authors.initials: MH
authors.lastname: Bestle
authors.forename: Thomas
authors.initials: T
authors.lastname: Mohr
authors.forename: Mads H
authors.initials: MH
authors.lastname: Andersen
authors.forename: Jesper
authors.initials: J
authors.lastname: Løken
authors.forename: Hamid
authors.initials: H
authors.lastname: Tousi
authors.forename: Peter
authors.initials: P
authors.lastname: Søe-Jensen
authors.forename: Anne Ø
authors.initials: AØ
authors.lastname: Lauritsen
authors.forename: Ditte
authors.initials: D
authors.lastname: Strange
authors.forename: John A
authors.initials: JA
authors.lastname: Petersen
authors.forename: Katrin
authors.initials: K
authors.lastname: Thormar
authors.forename: Kim M
authors.initials: KM
authors.lastname: Larsen
authors.forename: Niels-Erik
authors.initials: NE
authors.lastname: Drenck
authors.forename: Jannik
authors.initials: J
authors.lastname: Helweg-Larsen
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansen
authors.forename: Kristian
authors.initials: K
authors.lastname: Reinholdt
authors.forename: Jens K
authors.initials: JK
authors.lastname: Møller
authors.forename: Bente
authors.initials: B
authors.lastname: Olesen
authors.forename: Maiken C
authors.initials: MC
authors.lastname: Arendrup
authors.forename: Christian
authors.initials: C
authors.lastname: Østergaard
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.forename: Jesper
authors.initials: J
authors.lastname: Grarup
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
mesh_terms: D018806:APACHE; D000367:Age Factors; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D058365:Candidiasis, Invasive / Q000209:etiology*; D002444:Cefuroxime / Q000008:administration & dosage / Q000009:adverse effects; D002939:Ciprofloxacin / Q000008:administration & dosage / Q000009:adverse effects; D016638:Critical Illness / Q000628:therapy*; D003718:Denmark; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007362:Intensive Care Units / Q000706:statistics & numerical data*; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010878:Piperacillin / Q000008:administration & dosage / Q000009:adverse effects; D000077725:Piperacillin, Tazobactam Drug Combination; D016037:Single-Blind Method; D013845:Thienamycins / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077725:Piperacillin, Tazobactam Drug Combination; D002939:Ciprofloxacin; D010397:Penicillanic Acid; D000077731:Meropenem; D002444:Cefuroxime; D010878:Piperacillin