The Eagle-like effect of echinocandins: what’s in a name? Expert Rev. Anti Infect. Ther. 11(11), 1179–1191 (2013) Kim Vanstraelen* 1 , Katrien Lagrou 2 , Johan Maertens 3 , Joost Wauters 4 , Ludo Willems 1 and Isabel Spriet 1 1 Department of Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 2 Department of Microbiology and Immunology, Clinical Department of Laboratory Medicine, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 3 Clinical Department of Haematology, Acute Leukaemia and Stem Cell Transplantation Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium 4 Clinical Department of General Internal Medicine, Medical Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 3000 Leuven, Belgium *Author for correspondence: Tel.: +32 16 34 30 80 Fax: +32 16 34 30 84 kim.vanstraelen@uzleuven.be Despite several years of research, a lot of questions remain about the paradoxical attenuation of echinocandin activity against Candida and Aspergillus species at certain drug concentrations above the MIC values, the so-called paradoxical growth effect or Eagle-like effect. Although this phenomenon has been observed in several in vitro studies, confirming in vivo data are scarce. The clinical relevance remains unknown, although more and more data suggest that the clinical impact of this phenomenon might be heavily overrated. Detailed knowledge about the mechanisms responsible for this phenomenon and further research about the presence of the effect in the human body is necessary to decide whether the paradoxical growth effect of echinocandins can really interfere with an adequate treatment of invasive fungal diseases in clinical practice. KEYWORDS: anidulafungin • Aspergillus spp. • Candida spp. • caspofungin • Eagle effect • Eagle-like effect • echinocandins • micafungin • paradoxical growth The term ‘Eagle effect’, also called the para- doxical growth effect (PGE), refers to the phe- nomenon of reduced bactericidal or fungicidal activity at high concentrations of antibiotics or antifungals, mainly in in vitro circumstances. It has primarily been observed with b-lactam antibiotics and with echinocandins [1]. It is generally accepted that antibacterial activity is proportional to drug concentration and that an increasing bactericidal effect can be expected with increasing antimicrobial con- centrations [2]. However, during the past deca- des, several studies reported otherwise. As early as 1948, Eagle and Musselman found that Staphylococcus aureus, b-hemolytic Streptococci and Enterococcus faecalis species (spp.) were killed much slower by high concentrations of benzylpenicillin compared with lower concen- trations, which was called the ‘paradoxical zone phenomenon’ [1]. Today, this phenom- enon is often referred to as the ‘Eagle effect’, although it was first described by Kirby in 1945 and by Garrod in the same year and in 1948 [3–5]. These results were initially attrib- uted to impurities, which were often present in the penicillin preparations in those days [3,5]. Eagle and Musselman were the first to investigate this zone phenomenon more thoroughly in several bacterial organisms [1,6]. Except for penicillins, the PGE also seems to occur in vitro with quinolone antibiotics in the treatment of several bacterial species like Escherichia coli [7–11], E. faecalis [12], Proteus mirabilis [13] and S. aureus [14,15]. The effect has been documented mainly for nalidixic acid [7–10,13], but there are also reports about a paradoxical activity with ciprofloxacin [8,11,14,15], norfloxacin [8,15] and sparfloxacin [15]. Addi- tionally, the PGE was shown for pefloxa- cin [9,16] and temafloxacin [15], but they were withdrawn from the market because of safety issues, and for merafloxacin, which is not approved for clinical use [12]. Anno 2013, despite the investigation of sev- eral mechanisms, the antibiotic PGE is not yet completely elucidated. In 1952, Eagle pub- lished the following hypothesis: “the inflam- matory focus has become a less favorable medium for bacterial growth, either because of an inadequate supply of nutrients, because of the local accumulation of products toxic to the bacteria, or both. Since penicillin is known to affect only actively growing cells and to be ineffective on ‘resting’ cells, the organisms probably become less susceptible to its bacteri- cidal effect for the very reason that they are Review www.expert-reviews.com 10.1586/14787210.2013.841543 Ó 2013 Informa UK Ltd ISSN 1478-7210 1179 Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by K U Leuven on 01/10/14 For personal use only.