The potential of antimicrobials to induce thrombocytopenia in critically ill patients: data from a randomized controlled trial
Maria Egede Johansen, Jens-Ulrik Jensen, Morten Heiberg Bestle, Lars Hein, Anne Øberg Lauritsen, Hamid Tousi, Kim Michael Larsen, Jesper Løken, Thomas Mohr, Katrin Thormar, Pär I Johansson, Alessandro Cozzi-Lepri, Jens D Lundgren, Maria Egede Johansen, Jens-Ulrik Jensen, Morten Heiberg Bestle, Lars Hein, Anne Øberg Lauritsen, Hamid Tousi, Kim Michael Larsen, Jesper Løken, Thomas Mohr, Katrin Thormar, Pär I Johansson, Alessandro Cozzi-Lepri, Jens D Lundgren
Abstract
Background: Antimicrobial-induced thrombocytopenia is frequently described in the literature among critically ill patients. Several antimicrobials have been implicated, although experimental evidence to demonstrate causality is limited. We report, using a randomized trial, the potential of antimicrobials to induce thrombocytopenia.
Methods: Randomized trial allocated patients to antimicrobial treatment according to standard- of-care (SOC group) or drug-escalation in case of procalcitonin increases (high-exposure group). Patients were followed until death or day 28. Thrombocytopenia defined as absolute (platelet count ≤ 100 x 109/L) or relative (≥ 20% decrease in platelet count). Analyses were performed in the two randomized groups and as a merged cohort.
Results: Of the 1147 patients with platelet data available, 18% had absolute thrombocytopenia within the first 24 hours after admission to intensive care unit and additional 17% developed this complication during follow-up; 57% developed relative thrombocytopenia during follow-up. Absolute and relative thrombocytopenia day 1-4 was associated with increased mortality (HR: 1.67 [95% CI: 1.30 to 2.14]; 1.71 [95% CI: 1.30 to 2.30], P<0.0001, respectively). Patients in the high-exposure group received more antimicrobials including piperacillin/tazobactam, meropenem and ciprofloxacin compared with the SOC group, whereas cefuroxime was used more frequently in the SOC group (p<0.05). Risk of absolute and relative thrombocytopenia (RR: 0.9 [0.7-1.3], p=0.7439; 1.2 [1.0-1.4], p=0.06; respectively), as well as absolute platelet count (daily difference, high-exposure vs. SOC -1.7 [-3.8-0.5], p=0.14) was comparable between groups. In observational analyses, use of ciprofloxacin and piperacillin/tazobactam predicted risk of relative thrombocytopenia (vs. cefuroxime, RR: 2.08 [1.48-2.92]; 1.44 [1.10-1.89], respectively), however only ciprofloxacin were associated with a reduction in absolute platelet count (p=0.0005).
Conclusion: High exposure to broad-spectrum antimicrobials does not result in a reduction in thrombocytopenia in critically ill patients. However, single use of ciprofloxacin, and less so piperacillin/tazobactam, may contribute to a lower platelet count.
Trial registration: ClinicalTrials.gov NCT00271752 https://ichgcp.net/clinical-trials-registry/NCT00271752.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Strauss R, Wehler M, Mehler K, Kreutzer D, Koebnick C et al. (2002) Thrombocytopenia in patients in the medical intensive care unit: bleeding prevalence, transfusion requirements, and outcome. Crit Care Med 30: 1765-1771. doi:10.1097/00003246-200208000-00015. PubMed: .
- Vanderschueren S, De Weerdt A, Malbrain M, Vankersschaever D, Frans E et al. (2000) Thrombocytopenia and prognosis in intensive care. Crit Care Med 28: 1871-1876. doi:10.1097/00003246-200006000-00031. PubMed: .
- Thiolliere F, Serre-Sapin AF, Reignier J, Benedit M, Constantin JM et al. (2013) Epidemiology and outcome of thrombocytopenic patients in the intensive care unit: results of a prospective multicenter study. Intensive Care Med 39: 1460-1468. doi:10.1007/s00134-013-2963-3. PubMed: .
- Vandijck DM, Blot SI, De Waele JJ, Hoste EA, Vandewoude KH et al. (2010) Thrombocytopenia and outcome in critically ill patients with bloodstream infection. Heart Lung 39: 21-26. doi:10.1016/j.hrtlng.2009.07.005. PubMed: .
- François B, Trimoreau F, Vignon P, Fixe P, Praloran V et al. (1997) Thrombocytopenia in the sepsis syndrome: role of hemophagocytosis and macrophage colony-stimulating factor. Am J Med 103: 114-120. doi:10.1016/S0002-9343(97)00136-8. PubMed: .
- Rice TW, Wheeler AP (2009) Coagulopathy in critically ill patients: part 1: platelet disorders. Chest 136: 1622-1630. doi:10.1378/chest.08-2534. PubMed: .
- Aster RH, Bougie DW (2007) Drug-induced immune thrombocytopenia. N Engl J Med 357: 580-587. doi:10.1056/NEJMra066469. PubMed: .
- Kenney B, Stack G (2009) Drug-induced thrombocytopenia. Arch Pathol Lab Med 133: 309-314. PubMed: .
- Al-Nouri ZL, George JN (2012) Drug-induced thrombocytopenia: an updated systematic review, 2012. Drug Saf 35: 693-694. doi:10.2165/11633310-000000000-00000. PubMed: .
- Loo AS, Gerzenshtein L, Ison MG (2012) Antimicrobial drug-induced thrombocytopenia: a review of the literature. Semin Thromb Hemost 38: 818-829. doi:10.1055/s-0032-1328882. PubMed: .
- Reese JA, Li X, Hauben M, Aster RH, Bougie DW et al. (2010) Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 116: 2127-2133. doi:10.1182/blood-2010-03-276691. PubMed: .
- Visentin GP, Liu CY (2007) Drug-induced thrombocytopenia. Hematol Oncol Clin North Am 21: 685-696, vi
- Priziola JL, Smythe MA, Dager WE (2010) Drug-induced thrombocytopenia in critically ill patients. Crit Care Med 38: S145-S154. doi:10.1097/CCM.0b013e3181de0b88. PubMed: .
- Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT et al. (2011) Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med 39: 2048-2058. doi:10.1097/CCM.0b013e31821e8791. PubMed: .
- Cheah CY, De Keulenaer B, Leahy MF (2009) Fluoroquinolone-induced immune thrombocytopenia: a report and review. Intern Med J 39: 619-623. doi:10.1111/j.1445-5994.2009.01996.x. PubMed: .
- Rousan TA, Aldoss IT, Cowley BD Jr., Curtis BR, Bougie DW et al. (2010) Recurrent acute thrombocytopenia in the hospitalized patient: sepsis, DIC, HIT, or antibiotic-induced thrombocytopenia. Am J Hematol 85: 71-74. PubMed: .
- George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA et al. (1998) Drug-induced thrombocytopenia: a systematic review of published case reports. Ann Intern Med 129: 886-890. doi:10.7326/0003-4819-129-11_Part_1-199812010-00009. PubMed: .
- Chaudhry M, Tarneja N, Gundale A, Roa D, Levey R (2010) Bone marrow suppression: a side effect of ciprofloxacin therapy. Am J Ther 17: e167-e168. doi:10.1097/MJT.0b013e3181b442b9. PubMed: .
- Starr JA, Ragucci KR (2005) Thrombocytopenia associated with intravenous ciprofloxacin. Pharmacotherapy 25: 1030-1034. doi:10.1592/phco.2005.25.7.1030. PubMed: .
- Tuccori M, Guidi B, Carulli G, Blandizzi C, Del Tacca M et al. (2008) Severe thrombocytopenia and haemolytic anaemia associated with ciprofloxacin: a case report with fatal outcome. Platelets 19: 384-387. doi:10.1080/09537100801993040. PubMed: .
- Tomar GS, Agrawal RS, Kalyankar VB, Chawla S, Tiwari AK (2012) Piperacillin/tazobactem induced epistaxis- A case report. J Anaesthesiol Clin Pharmacol 28: 404-405. doi:10.4103/0970-9185.98368. PubMed: .
- Lin SY, Huang JC, Shen MC, Chuang SH, Lee MH et al. (2012) Piperacillin-induced thrombocytopenia reversed by high-flux hemodialysis in an uremic patient. Hemodial Int 16 Suppl 1: S50-S53. doi:10.1111/j.1542-4758.2012.00745.x. PubMed: .
- Anand A, Chauhan HK (2011) Piperacillin and vancomycin induced severe thrombocytopenia in a hospitalized patient. Platelets.
- Garbe E, Andersohn F, Bronder E, Salama A, Klimpel A et al. (2012) Drug-induced immune thrombocytopaenia: results from the Berlin Case-Control Surveillance Study. Eur J Clin Pharmacol 68: 821-832. doi:10.1007/s00228-011-1184-3. PubMed: .
- Gasser TC, Ebert SC, Graversen PH, Madsen PO (1987) Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function. Antimicrob Agents Chemother 31: 709-712. doi:10.1128/AAC.31.5.709. PubMed: .
- Nicolle LE (1999) Quinolones in the aged. Drugs 58 Suppl 2: 49-51. doi:10.2165/00003495-199958002-00009. PubMed: .
- Surana SP, Sardinas Z, Multz AS (2012) Moxifloxacin (avelox) induced thrombotic thrombocytopenic purpura. Case Rep Med 2012: 459140
- Campi P, Pichler WJ (2003) Quinolone hypersensitivity. Curr Opin Allergy Clin Immunol 3: 275-281. doi:10.1097/00130832-200308000-00007. PubMed: .
- Akca S, Haji-Michael P, de Mendonça A, Suter P, Levi M et al. (2002) Time course of platelet counts in critically ill patients. Crit Care Med 30: 753-756. doi:10.1097/00003246-200204000-00005. PubMed: .
- Fitzgerald JR, Foster TJ, Cox D (2006) The interaction of bacterial pathogens with platelets. Nat Rev Microbiol 4: 445-457. doi:10.1038/nrmicro1425. PubMed: .
- Li Z, Yang F, Dunn S, Gross AK, Smyth SS (2011) Platelets as immune mediators: Their role in host defense responses and sepsis. Thromb Res 127: 184-188. doi:10.1016/j.thromres.2010.10.010. PubMed: .
- Moreau D, Timsit JF, Vesin A, Garrouste-Orgeas M, de Lassence A et al. (2007) Platelet count decline: an early prognostic marker in critically ill patients with prolonged ICU stays. Chest 131: 1735-1741. doi:10.1378/chest.06-2233. PubMed: .
- Arepally GM, Ortel TL (2006) Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 355: 809-817. doi:10.1056/NEJMcp052967. PubMed: .
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