Log in | Register

Antifungal de-escalation was not associated with adverse outcome in critically ill patients treated for invasive candidiasis: post hoc analyses of the AmarCAND2 study data

Sébastien Bailly| Olivier Leroy| Philippe Montravers| Jean-Michel Constantin| Hervé Dupont| Didier Guillemot| Olivier Lortholary| Jean-Paul Mira| Pierre-François Perrigault| Jean-Pierre Gangneux| Elie Azoulay| Jean-François Timsit
Original
Volume 41, Issue 11 / November , 2015

Pages 1931 - 1940

Abstract

Purpose

Systemic antifungal therapy (SAT) of invasive candidiasis needs to be initiated immediately upon clinical suspicion. Controversies exist about adequate time and potential harm of antifungal de-escalation (DE) in documented and suspected candidiasis in ICU patients. Our objective was to investigate whether de-escalation within 5 days of antifungal initiation is associated with an increase of the 28-day mortality in SAT-treated non-neutropenic adult ICU patients.

Methods

From the 835 non-neutropenic adults recruited in the multicenter prospective observational AmarCAND2 study, we selected the patients receiving systemic antifungal therapy for a documented or suspected invasive candidiasis in the ICU and who were still alive 5 days after SAT initiation. They were included into two groups according to the occurrence of observed SAT de-escalation before day 6. The average causal SAT de-escalation effect on 28-day mortality was evaluated by using a double robust estimation.

Results

Among the 647 included patients, early de-escalation at day 5 after antifungal initiation occurred in 142 patients (22 %), including 48 (34 %) patients whose SAT was stopped before day 6. After adjustment for the baseline confounders, early SAT de-escalation was the solely factor not associated with increased 28-day mortality (RR 1.12, 95 % CI 0.76–1.66).

Conclusion

In non-neutropenic critically ill adult patients with documented or suspected invasive candidiasis, SAT de-escalation within 5 days was not related to increased day-28 mortality but it was associated with decreased SAT consumption. These results suggest for the first time that SAT de-escalation may be safe in these patients.

Keywords

References

  1. Rangel-Frausto MS, Wiblin T, Blumberg HM, Saiman L, Patterson J, Rinaldi M, Pfaller M, Edwards JE, Jarvis W, Dawson J, Wenzel RP (1999) National epidemiology of mycoses survey (NEMIS): variations in rates of bloodstream infections due to Candida species in seven surgical intensive care units and six neonatal intensive care units. Clin Infect Dis 29:253–258
    • View reference on publisher's website
    • View reference on PubMed
  2. Tabah A, Koulenti D, Laupland K, Misset B, Valles J, Bruzzi de Carvalho F, Paiva JA, Cakar N, Ma X, Eggimann P, Antonelli M, Bonten MJM, Csomos A, Krueger WA, Mikstacki A, Lipman J, Depuydt P, Vesin A, Garrouste-Orgeas M, Zahar J-R, Blot S, Carlet J, Brun-Buisson C, Martin C, Rello J, Dimopoulos G, Timsit J-F (2012) Characteristics and determinants of outcome of hospital-acquired bloodstream infections in intensive care units: the EUROBACT International Cohort Study. Intensive Care Med 38:1930–1945
  3. Blumberg HM, Jarvis WR, Soucie JM, Edwards JE, Patterson JE, Pfaller MA, Rangel-Frausto MS, Rinaldi MG, Saiman L, Wiblin RT, Wenzel RP (2001) Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS Prospective Multicenter Study. Clin Infect Dis 33:177–186
    • View reference on publisher's website
    • View reference on PubMed
  4. Bassetti M, Righi E, Ansaldi F, Merelli M, Trucchi C, Cecilia T, De Pascale G, Diaz-Martin A, Luzzati R, Rosin C, Lagunes L, Trecarichi EM, Sanguinetti M, Posteraro B, Garnacho-Montero J, Sartor A, Rello J, Rocca GD, Antonelli M, Tumbarello M (2014) A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med 40:839–845
  5. Garrouste-Orgeas M, Timsit JF, Tafflet M, Misset B, Zahar J-R, Soufir L, Lazard T, Jamali S, Mourvillier B, Cohen Y, De Lassence A, Azoulay E, Cheval C, Descorps-Declere A, Adrie C, Costa de Beauregard M-A, Carlet J, OUTCOMEREA Study Group (2006) Excess risk of death from intensive care unit-acquired nosocomial bloodstream infections: a reappraisal. Clin Infect Dis 42:1118–1126
  6. Kollef M, Micek S, Hampton N, Doherty JA, Kumar A (2012) Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis 54:1739–1746
    • View reference on publisher's website
    • View reference on PubMed
  7. Pittet D, Li N, Woolson RF, Wenzel RP (1997) Microbiological factors influencing the outcome of nosocomial bloodstream infections: a 6-year validated, population-based model. Clin Infect Dis 24:1068–1078
    • View reference on publisher's website
    • View reference on PubMed
  8. Wisplinghoff H, Seifert H, Tallent SM, Bischoff T, Wenzel RP, Edmond MB (2003) Nosocomial bloodstream infections in pediatric patients in United States hospitals: epidemiology, clinical features and susceptibilities. Pediatr Infect Dis J 22:686–691
    • View reference on publisher's website
    • View reference on PubMed
  9. Grim SA, Berger K, Teng C, Gupta S, Layden JE, Janda WM, Clark NM (2012) Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: correlation with outcomes. J Antimicrob Chemother 67:707–714
    • View reference on publisher's website
    • View reference on PubMed
  10. Köck R, Eißing LC, Boschin MG, Ellger B, Horn D, Idelevich EA, Becker K (2013) Evaluation of bactec mycosis IC/F and Plus Aerobic/F blood culture bottles for detection of Candida in the presence of antifungal agents. J Clin Microbiol 51:3683–3687
    • View reference on publisher's website
    • View reference on PubMed
  11. Eggimann P, Pittet D (2014) Candida colonization index and subsequent infection in critically ill surgical patients: 20 years later. Intensive Care Med 40:1429–1448
  12. Azoulay E, Dupont H, Tabah A, Lortholary O, Stahl J-P, Francais A, Martin C, Guidet B, Timsit J-F (2012) Systemic antifungal therapy in critically ill patients without invasive fungal infection. Crit Care Med 40:813–822
    • View reference on publisher's website
    • View reference on PubMed
  13. Alexander BD, Johnson MD, Pfeiffer CD, Jiménez-Ortigosa C, Catania J, Booker R, Castanheira M, Messer SA, Perlin DS, Pfaller MA (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis 56:1724–1732
    • View reference on publisher's website
    • View reference on PubMed
  14. Saraya T, Tanabe K, Araki K, Yonetani S, Makino H, Watanabe T, Tsujimoto N, Takata S, Kurai D, Ishii H, Miyazaki Y, Takizawa H, Goto H (2014) Breakthrough invasive Candida glabrata in patients on micafungin: a novel FKS gene conversion correlated with sequential elevation of MIC. J Clin Microbiol 52:2709–2712
    • View reference on publisher's website
    • View reference on PubMed
  15. Ostrosky-Zeichner L, Shoham S, Vazquez J, Reboli A, Betts R, Barron MA, Schuster M, Judson MA, Revankar SG, Caeiro JP, Mangino JE, Mushatt D, Bedimo R, Freifeld A, Nguyen MH, Kauffman CA, Dismukes WE, Westfall AO, Deerman JB, Wood C, Sobel JD, Pappas PG (2014) MSG-01: a randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis 58:1219–1226
    • View reference on publisher's website
    • View reference on PubMed
  16. León C, Ruiz-Santana S, Saavedra P, Galván B, Blanco A, Castro C, Balasini C, Utande-Vázquez A, González de Molina FJ, Blasco-Navalproto MA, López MJ, Charles PE, Martín E, Hernández-Viera MA, Cava Study Group (2009) Usefulness of the “Candida score” for discriminating between Candida colonization and invasive candidiasis in non-neutropenic critically ill patients: a prospective multicenter study. Crit Care Med 37:1624–1633
  17. Ostrosky-Zeichner L, Sable C, Sobel J, Alexander BD, Donowitz G, Kan V, Kauffman CA, Kett D, Larsen RA, Morrison V, Nucci M, Pappas PG, Bradley ME, Major S, Zimmer L, Wallace D, Dismukes WE, Rex JH (2007) Multicenter retrospective development and validation of a clinical prediction rule for nosocomial invasive candidiasis in the intensive care setting. Eur J Clin Microbiol Infect Dis 26:271–276
    • View reference on publisher's website
    • View reference on PubMed
  18. Bailly S, Bouadma L, Azoulay E, Orgeas MG, Adrie C, Souweine B, Schwebel C, Maubon D, Hamidfar-Roy R, Darmon M, Wolff M, Cornet M, Timsit J-F (2015) Failure of empirical systemic antifungal therapy in mechanically ventilated critically ill patients. Am J Respir Crit Care Med 191:1139–1146
    • View reference on publisher's website
    • View reference on PubMed
  19. Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ, Lortholary O, Meersseman W, Akova M, Arendrup MC, Arikan-Akdagli S, Bille J, Castagnola E, Cuenca-Estrella M, Donnelly JP, Groll AH, Herbrecht R, Hope WW, Jensen HE, Lass-Flörl C, Petrikkos G, Richardson MD, Roilides E, Verweij PE, Viscoli C, Ullmann AJ, ESCMID Fungal Infection Study Group (2012) ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 18(Suppl 7):19–37
  20. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE, Filler SG, Fisher JF, Kullberg B-J, Ostrosky-Zeichner L, Reboli AC, Rex JH, Walsh TJ, Sobel JD, Infectious Diseases Society of Americia (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535
  21. Vazquez J, Reboli AC, Pappas PG, Patterson TF, Reinhardt J, Chin-Hong P, Tobin E, Kett DH, Biswas P, Swanson R (2014) Evaluation of an early step-down strategy from intravenous anidulafungin to oral azole therapy for the treatment of candidemia and other forms of invasive candidiasis: results from an open-label trial. BMC Infect Dis 14:97
    • View reference on publisher's website
    • View reference on PubMed
  22. Takesue Y, Ueda T, Mikamo H, Oda S, Takakura S, Kitagawa Y, Kohno S, ACTIONs Project (2015) Management bundles for candidaemia: the impact of compliance on clinical outcomes. J Antimicrob Chemother 70:587–593
  23. Bang H, Robins JM (2005) Doubly robust estimation in missing data and causal inference models. Biometrics 61:962–973
    • View reference on publisher's website
    • View reference on PubMed
  24. Bailly S, Pirracchio R, Timsit JF (2015) What’s new in the quantification of causal effects from longitudinal cohort studies: a brief introduction to marginal structural models for intensivists. Intensive Care Med. doi:10.1007/s00134-015-3919-6
  25. Zhang M, Schaubel DE (2012) Contrasting treatment-specific survival using double-robust estimators. Stat Med 31:4255–4268
    • View reference on publisher's website
    • View reference on PubMed
  26. Funk MJ, Westreich D, Wiesen C, Stürmer T, Brookhart MA, Davidian M (2011) Doubly robust estimation of causal effects. Am J Epidemiol 173:761–767
    • View reference on publisher's website
    • View reference on PubMed
  27. Lortholary O, Renaudat C, Sitbon K, Madec Y, Denoeud-Ndam L, Wolff M, Fontanet A, Bretagne S, Dromer F, French Mycosis Study Group (2014) Worrisome trends in incidence and mortality of candidemia in intensive care units (Paris area, 2002–2010). Intensive Care Med 40:1303–1312
  28. Andes D, Forrest A, Lepak A, Nett J, Marchillo K, Lincoln L (2006) Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans. Antimicrob Agents Chemother 50:2374–2383
    • View reference on publisher's website
    • View reference on PubMed
  29. Fekkar A, Dannaoui E, Meyer I, Imbert S, Brossas JY, Uzunov M, Mellon G, Nguyen S, Guiller E, Caumes E, Leblond V, Mazier D, Fievet MH, Datry A (2014) Emergence of echinocandin-resistant Candida spp. in a hospital setting: a consequence of 10 years of increasing use of antifungal therapy? Eur J Clin Microbiol Infect Dis 33:1489–1496
    • View reference on publisher's website
    • View reference on PubMed
  30. Khan Z, Ahmad S, Joseph L, Al-Obaid K (2014) Isolation of cholesterol-dependent, multidrug-resistant Candida glabrata strains from blood cultures of a candidemia patient in Kuwait. BMC Infect Dis 14:188
    • View reference on publisher's website
    • View reference on PubMed
  31. Lewis JS, Wiederhold NP, Wickes BL, Patterson TF, Jorgensen JH (2013) Rapid emergence of echinocandin resistance in Candida glabrata resulting in clinical and microbiologic failure. Antimicrob Agents Chemother 57:4559–4561
    • View reference on publisher's website
    • View reference on PubMed
  32. Shields RK, Nguyen MH, Press EG, Updike CL, Clancy CJ (2013) Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. Antimicrob Agents Chemother 57:3528–3535
    • View reference on publisher's website
    • View reference on PubMed
  33. Bizerra FC, Jimenez-Ortigosa C, Souza ACR, Breda GL, Queiroz-Telles F, Perlin DS, Colombo AL (2014) Breakthrough candidemia due to multidrug-resistant Candida glabrata during prophylaxis with a low dose of micafungin. Antimicrob Agents Chemother 58:2438–2440
    • View reference on publisher's website
    • View reference on PubMed
  34. Bal AM, Shankland GS, Scott G, Imtiaz T, Macaulay R, McGill M (2014) Antifungal step-down therapy based on hospital intravenous to oral switch policy and susceptibility testing in adult patients with candidaemia: a single centre experience. Int J Clin Pract 68:20–27
    • View reference on publisher's website
    • View reference on PubMed
  35. Tissot F, Lamoth F, Hauser PM, Orasch C, Flückiger U, Siegemund M, Zimmerli S, Calandra T, Bille J, Eggimann P, Marchetti O (2013) Beta-glucan antigenemia anticipates diagnosis of blood culture-negative intraabdominal candidiasis. Am J Respir Crit Care Med 188:1100–1109
    • View reference on publisher's website
    • View reference on PubMed
  36. Poissy J, Sendid B, Damiens S, Ichi Ishibashi K, François N, Kauv M, Favory R, Mathieu D, Poulain D (2014) Presence of Candida cell wall derived polysaccharides in the sera of intensive care unit patients: relation with candidaemia and Candida colonisation. Crit Care 18:R135
    • View reference on publisher's website
    • View reference on PubMed

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement