Clinical Investigations

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 S. MD, PhD^1,2; Hein, Lars MD^3,4; Lundgren, Bettina MD, DMSc^2,5; Bestle, Morten H. MD, PhD³; Mohr, Thomas MD, PhD⁶; Andersen, Mads H. MD⁷; Løken, Jesper MD⁸; Tousi, Hamid MD⁹; Søe-Jensen, Peter MD⁹; Lauritsen, Anne Ø. MD⁴; Strange, Ditte MD⁴; Petersen, John A. MD⁸; Thormar, Katrin MD⁶; Larsen, Kim M. MD¹⁰; Drenck, Niels-Erik MD¹¹; Helweg-Larsen, Jannik MD, DMSc¹; Johansen, Maria E. MD¹; Reinholdt, Kristian MD¹; Møller, Jens K. MD, DMSc¹²; Olesen, Bente MD, PhD¹³; Arendrup, Maiken C. MD, PhD¹⁴; Østergaard, Christian MD, PhD, DMSc^2,15; Cozzi-Lepri, Alessandro MSc, PhD^1,16; Grarup, Jesper DVM¹; Lundgren, Jens D. MD, DMSc¹ for the Procalcitonin and Survival Study Group

Author Information

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.

* See also p. 708.

Participating investigators for the Procalcitonin And Survival Study Group are listed in the Appendix 1.

The trial has been approved by the regional ethics committee (H-KF-272–753) and adheres to the Helsinki declaration, revised in Seoul 2008.

Drs. Jensen and Lundgren had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. They drafted the article. Drs. Jensen, Cozzi-Lepri, and Lundgren did statistical analysis. Drs. Jensen, Lundgren, and Lundgren obtained funding. All authors contributed substantially to conception and design, or acquisition of data, or analysis and interpretation of data, and administrative, technical, or material support. All other authors revised it critically for important intellectual content. All authors gave final approval of the version to be published.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the Danish Research Agency (Danish State), the Lundbeck Foundation, Research Foundation for the Capital Region of Denmark, the Toyota Foundation, Brahms diagnostica (unrestricted grant), the Harboe Foundation, the A.P. Møller Foundation, and the Idella Foundation. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the article.Dr. Jensen reports on behalf of Copenhagen University Hospital and received grants for the submitted work from the Danish Research Council (Danish State), the Lundbeck Foundation, the Toyota Foundation, Brahms diagnostic, the Idella Foundation, the Harboe Foundation and the Capital Region of Copenhagen Research Foundation. All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf.

The authors received support for article research from the Danish State and Lundbeck Foundation.

For information regarding this article, E-mail: [email protected]

Critical Care Medicine 43(3):p 594-602, March 2015. | DOI: 10.1097/CCM.0000000000000746

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.