Cardiac Impairment in Therapy with Fluoroquinolones (pp. 189-212)
Authors: (Thomas Kibbel, Hasib Djonlagić, Sven Suefke, Medical Department I, University Clinic Schleswig-Holstein, Campus Luebeck, Germany)
Abstract: Background: Fluoroquinolones may exert a variety of adverse effects. Regarding this concern, cardiotoxic alterations are obtaining more interest. Because typically described torsades de pointes tachycardia (TdP) are usually found only in rare cases we looked for other surrogates. Also discussed is how the oxidative stress, mainly found in respect to an Achilles tendon rupture, could be relevant on several organ functions.
Methods: We evaluated data on 204 patients (78 female / 126 male, 61.1±16.1 years) with severe bacterial infections. 133 patients received also QTc-prolonging drugs and 71 only β lactames. In 57.9% ciprofloxacin (n=45) or (respectively 3 times and) levofloxacin (n=35) was at least the temporary leading agent for antimicrobial treatment. Simultaneously, 47 patients received one or two macrolides (35.3%), 50 received fluconazole (37.6) and 18 received other QTc prolonging agents (13.5%). At that, in 56 of the 133 patients (42.1%) had more than one QTc-prolonging drug used during the therapy course (2 drugs: n=44; ≥3 drugs: n=12). Excluding data on patients that received either both substance classes or, respectively, both fluoroquinolones, we first evaluated fluoroquinolones vs. macrolides and then levofloxacin vs. ciprofloxacin. For getting more information, we looked whether gender, age and body weight have influence on the outcome in patients receiving QTc-prolonging agents. Furthermore, we analyzed incidence of arrhythmias and causes leading to death.
Results: Although no significant specific difference on substances was found, the results confirmed epidemic data that risk decreased as follows: macrolides > levofloxacin > ciprofloxacin > β lactames. As such, the Standardized Mortality Ratio (SMR) decreased from 0.918, 0.713 and 0.634 to 0.588. If ≥2 QTc-prolonging antibiotic drugs were used, the SMR accounted to 0.977. Additionally fluconazole was given in 21.7% (macrolides) until 38.5% (ciprofloxacin). As a result, persistent ventricular fibrillation occurred in only two cases. However, by comparable severity of illness and comparable effect of antibiotic therapy, age, QTc-prolonging drugs (mostly macrolides and/or fluoroquinolones) and less body weight,only in women showed significant effects on survival (p<0.001, 0.008 and 0.009, respectively). In women, the best risk assessment (i.e., discrimination survival vs. non-survival) was achieved if the latter factors were combined (p<0.001). In a direct comparison to men, women with at least two factors had a significantly poorer outcome (OR 2.37; 95% CI 1.13–4.98; p=0.022). With regard to ascertained QT-related arrhythmias, especially those of a ventricular origin, such episodes may be interpreted as signs of cardiac impairment or as precursors of thromboembolic events (acute stroke, acute lung embolism, acute mesenteric infarction). As such, causes leading to death explaining cardiac impairment were more found in patients receiving QTc-prolonging drugs: overall (OR [95% CI] = 6.7 [1.86-24.2]; p=0.002) and in women comparatively to men (OR [95% CI] = 3.88 [1.06-14.2]; p=0.034).
Conclusions: Our results harmonize with data that macrolides are of greater risk than fluoroquinolones (levofloxacin > ciprofloxacin) and both are of greater risk than β lactames. By the precondition that antibiotic response in the critically ill must be secured first, secondly, a QTc monitoring should be performed for a patient´s safety. However, when on fluoroquinolones it must be considered that not only a QTc-prolonging effect may be responsible for, also an increase of oxidative stress could lead, at least partially, to impaired cardiac function and worse outcome. Nonetheless, because QTc prolongation, as well as the production of reactive oxygen species, is dependent from achieved concentration, the dosage of relevant drugs should be adjusted not only to organ function, but also to body weight (or perhaps rather to body surface area). This aspect is especially important in elderly lean women.
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