The Problem of Culture-Negative Infections

Because modern medicine suffers increasingly from the “silo” phenomenon, in which each specialty ponders its problems in isolation, the gradual emergence of a generalized threat to millions of patients is thus poorly countered by the disconnected efforts of small teams that address the same theme without the recognition of common ground. The recent recognition that bacteria have reverted to their natural biofilm strategy (Costerton 2007) in attacking human hosts, in response to advances in immunization (vaccines) and therapy (antibiotics), has been perceived in a piecemeal fashion that is slowly spreading amongst the silos. We respond to medical threats in relation to the immediacy of the dangers to the patient, so the first reaction was to the phenomenal resistance of biofilm infections to antibiotics and to host defense mechanisms, and the past three decades have seen a series of tactical maneuvers involving surgical resection and high-dose antibiotic therapy. While medicine reacted to this serious threat of overt bacterial infections that were not prevented by vaccination, and that persisted in spite of seemingly suitable antibiotic therapy, another equally serious biofilm problem was emerging at the bottoms of several silos. Experienced clinicians in many specialties saw cases in which they were certain that bacteria were involved, because all of the classical signs of infection were present, but the gold standard of diagnosis (culture) was negative. Some of these cases involved medical devices (Khoury et al. 1992), others involved infections of compromised tissues (Hoiby 2002), but the overall fight, conducted in isolation in many silos, was to decide on the correct antibacterial G.D. Ehrlich (*) • J.W. Costerton Center for Genomic Sciences, Allegheny-Singer Research Institute, 320 East North Avenue, Pittsburgh, PA 15212, USA e-mail: [email protected] P.J. DeMeo Department of Orthopedic Surgery, Allegheny General Hospital, Pittsburgh, PA, USA G.D. Ehrlich et al. (eds.), Culture Negative Orthopedic Biofilm Infections, Springer Series on Biofilms 7, DOI 10.1007/978-3-642-29554-6_1, # Springer-Verlag Berlin Heidelberg 2012 1 strategy when the bacterial etiology of many important diseases (otitis media, prostatitis) was called into question by negative cultures. Bacteria do not respect the silos created by clinicians and scientists. They have switched from an acute frontal attack by planktonic cells, to a strategy of biofilm growth and chronic attack on infected tissues, and the most serious long-term effect of this tactical change may be that they evade detection by the classic methods of Medical Microbiology. 1 Silos in Clinical Medicine It may be instructive to examine one particular medical silo (Ear, Nose and Throat 1⁄4 ENT) because the biofilm concept and the most refined molecular diagnostic capability came together in the team of Chris Post and Garth Ehrlich in that specialty. Culture data from otitis media with effusion (OME) were so consistently negative that some practitioners had suggested that it was a nonspecific inflammatory condition, and the basic bacterial etiology of the disease was cast into doubt. Clusters of bacterial cells could be seen by direct microscopy in the effusions from the ears of these patients, and DNA-based PCRmethods (Post et al. 1995) showed the presence of very large amounts of DNA from the three major putative pathogens that occasionally grew in culture. When questions were raised about the viability of the bacteria in the effusions from the middle ear, the team used reverse transcriptase (RT)PCR to detect short-lived messenger RNA (Rayner et al. 1998) to prove that the bacterial pathogens were both present and alive at the time of sampling, which allayed suspicions that antibiotic therapy alone could account for the negative cultures. In an elegant “coup de grace,” the team then provided direct microscopic and molecular evidence (Hall-Stoodley et al. 2006) that OME is caused by bacteria growing in biofilms in the middle ear and that culture negativity is just as much a characteristic of this biofilm disease as is resistance to antibiotics and host defenses. In another silo (chronic wounds) the expert application of modern molecular techniques (Dowd et al. 2008) has proved that cultures only detect a small proportion of the bacterial and fungal species that are actually present, and that the clinical management of these complex infections can be radically improved using this accurate and pertinent information. The inference from these scattered examples is disturbing because, if biofilm infections are indeed significantly more difficult to detect by conventional culture methods, tens of millions of patients are at risk for missed diagnoses. The CDC and the NIH have estimated that biofilm infections now constitute 65 and 80 % (respectively) of bacterial infections treated by physicians in the developed world, and a recent publication reports (Wolcott et al. 2010) that these infections affect 14 million, and kill > 400,000, Americans each year. Culture methods are the only FDA-approved and universally available technology for the detection and identification of bacterial and fungal infections in most of the developed world. In view of these well documented failure of cultures to detect such common biofilm 2 G.D. Ehrlich et al.