For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Infectious Diseases Vol 3 April 2003 http://infection.thelancet.com 223 It can be difficult to establish whether a febrile episode in a patient is suggestive of an infectious or non-infectious cause. Besides clinical history, physical examination, and laboratory assays, scintigraphic imaging of bacterial and fungal infections using antimicrobial peptides labelled with technetium-99m ( 99m Tc) can be useful. Key to this latter approach is that some of these peptides accumulate at sites of infection but not in sterile inflammatory lesions, because of their preferential binding to bacteria and fungi over mammalian cells. Here we report on imaging of infections with these peptides in laboratory animals. On the basis of their favourable binding characteristics, fast and easy penetration into the infected area, and rapid clearance from the circulation (half-life ~30 min) via the kidneys, several 99m Tc-antimicrobial peptides have been selected that distinguish infectious foci from sites of sterile inflammation. Accumulation of 99m Tc-antimicrobial peptides at sites of experimental infection correlated well with the number of viable bacteria/yeasts present. This finding allowed us to monitor with 99m Tc-antimicrobial peptides the efficacy of antimicrobial therapy in animals with experimental infections. In conclusion, non-microbicidal amounts of 99m Tc-antimicrobial peptides are promising candidates for the scintigraphic imaging of bacterial/fungal infections and for monitoring the efficacy of antimicrobial therapy in patients. Lancet Infect Dis 2003; 3: 223–29 When confronted with a febrile patient the clinician establishes on the basis of medical history, physical examination, laboratory tests, and imaging studies whether signs and symptoms are suggestive of an infectious or non- infectious cause. After identification of the putative site of infection microbiological cultures of body fluids or biopsies are undertaken to identify the pathogen(s). Studies indicated that more than 85% of patients referred to hospital by their primary-care physician are febrile due to an infection. 1 However, in patients with a serious underlying condition fewer than a half of febrile episodes can be attributed to infections. 2 Moreover, in these critically ill patients clinical manifestations of infection are often subtle, non-typical, or non-existent, yet the identification of an infection at an early stage of the disease is critical for a favourable outcome. 1,3,4 Most current laboratory tests used to guide the diagnostic process rely on factors involved in the inflammatory host response—eg, erythrocyte sedimentation rate, white-blood-cell count, acute-phase proteins, and cytokines—but will never be specific enough to discriminate between infection and inflammation. In this connection, nuclear medicine could make an important contribution provided that tracers discriminating infections from sterile inflammations are available. Unfortunately, current radio- pharmaceuticals accumulate in both infected and inflamed areas due to non-specific mechanisms of accumulation. 5 Among these are gallium-67-citrate ( 67 Ga), indium-111 ( 111 In), or technetium-99m ( 99m Tc)-labelled polyclonal human immunoglobulins, and 111 In-labelled or 99m Tc- labelled autologous leucocytes. Other agents interact with receptors or domains on infiltrating leucocytes, such as 99m Tc-labelled antigranulocyte monoclonal antibodies (or fragments thereof) and 99m Tc-labelled chemotactic peptides and interleukins. 6 Since antimicrobial peptides often display preferential binding to microorganisms, promising radiopharmaceuticals for discriminating infections from inflammations may be recruited from the array of human antimicrobial peptides/proteins. 7–11 In this review we summarise the current knowledge of antimicrobial peptides and examine the available information on the use of those peptides that, after radiolabelling, can visualise infections in both immunocompetent and immunocompromised animals, and monitor the efficacy of antimicrobial therapy in animals with an experimental infection. Antimicrobial peptides The first report on antimicrobial proteins—ie, lactoferrin and histones—dates back to 1930, 12 but the discovery of antibiotics, which were much easier to synthesise, drew the attention of researchers away from these antimicrobial proteins. Due to the development of microorganisms resistant to the most widely used antibiotics and antifungal agents, antimicrobial peptides have gained renewed attention as possible therapeutic candidates. 7 The discovery of antimicrobial peptides, such as cecropin from pupae of giant silk moths, 13 magainins from xenopus skin, 14 Review Radiolabelled antimicrobial peptides AL and PHN are at the Department of Infectious Diseases, Leiden University Medical Center (LUMC), Leiden, Netherlands. AL is also at the Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Università degli Studi di Pisa, Pisa, Italy; and MMW and EKJP are at the Department of Radiology, Division of Nuclear Medicine, LUMC, Netherlands. Correspondence: Dr EKJ Pauwels, Department of Radiology, Division of Nuclear Medicine, Leiden University Medical Center, C4-Q, PO Box 9600, NL-2300 RC Leiden, Netherlands. Tel +31 71 5263475; fax +31 71 5266751; email E.K.J.Pauwels@lumc.nl Radiolabelled antimicrobial peptides for infection detection Antonella Lupetti, Mick M Welling, Ernest K J Pauwels, and Peter H Nibbering