The Potential of Antimicrobials to Induce Thrombocytopenia in Critically Ill Patients: Data from a Randomized Controlled Trial

<div><p>Background</p><p>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.</p> <p>Methods</p><p>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 ≤100x109/L) or relative (≥20% decrease in platelet count). Analyses were performed in the two randomized groups and as a merged cohort. </p> <p>Results</p><p>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). </p> <p>Conclusion</p><p>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.</p> <p>Trial Registration</p><p><a href="http://clinicaltrials.gov" target="_blank">ClinicalTrials.gov</a> NCT00271752 <a href="http://clinicaltrials.gov/ct2/show/nct00271752" target="_blank">http://clinicaltrials.gov/ct2/show/NCT00271752</a></p> </div

Estimated change in daily platelet count.

<div><p>Mixed model adjusted for the following time fixed variables: randomisation group, age, gender, BMI, severe sepsis/septic shock at ICU admission, APACHE II score, surgical vs. medical patients. </p> <p>Time-updated use of antimicrobials was included in the model.</p> <p>Ciprofloxacin, Piperacillin/tazobactam (pip/tazo) (used alone or in combinations not including cefuroxime) and none (no antimicrobials) compared to people receiving cefuroxime (used alone or in combinations non including the antibiotic in question).</p></div

Use of frequent prescribed antimicrobials in the PASS study and occurrence of absolute and relative thrombocytopenia among the two randomized groups.

<div><p>Unadjusted analysis displaying the use of antimicrobials and occurrence of thrombocytopenia among the two randomized groups displayed as relative rate ratio (RR) during 28 day follow-up.</p> <p>Absolute (one platelet count < 100 x 109/L) or relative (>=20 % decrease in platelet count from ICU admission) thrombocytopenia.</p> <p>RR-Ratio >1.0 indicates that the high-ex. group have a relatively higher risk of occurrence of the asses variable and RR-Ratio <1.0 indicates relatively higher risk of patients in the SOC group of occurrence of the asses variable. RR-ratio=0 indicates no difference between the two groups. </p></div