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Unmet Medical Needs in Life-Threatening Infections - Caring for the Critically Ill

Michael Bauer Andreas Kortgen, and Mervyn Singer

1.1 Life Threatening Infections and Sepsis - Defining the Problem

The large number of infectious agents, complicated further by many varied pathogen- and host-specific characteristics, results in a broad spectrum of communicable diseases of which both prevention and control are challenging. While many infectious diseases are benign and are primarily treated in the community, severe infections may give rise to an urgent need to control the source of infection, to implement appropriate anti-infective therapy, and to provide supportive care to maintain homeostasis [1].

Under these conditions, the patient outcome from infection is determined not only by the invading pathogen which can be directly toxic and destructive to cells and tissues but also - or even primarily - by the host response. This host response may be inappropriately exaggerated, leading to severe tissue injury. Here, the effector molecules of immune cells, such as oxygen free-radicals and nitric oxide, cannot discriminate between microbial targets and host tissue [2]. Indeed, a novel concept has been proposed to describe the development of organ failure, that is, severe sepsis, as a disturbed "disease tolerance" where the eventual development of organ dysfunction is considered an inability to establish an appropriate equilibrium between direct pathogen damage and the ensuing host response (Figure 1.1) [3]. Patients with an uncontrolled focus of infection or an exuberant host response are particularly prone to develop organ dysfunction requiring care in a specialized "intensive care unit (ICU)." Such patients are referred to as septic (Figure 1.2).

Figure 1.1 Evolving concepts of sepsis as a "host defense failure disease." The host response to invading pathogens requires a cytotoxic response that can result in a trade-off where tolerance of a pathogen may be associated with less organ injury.

Figure 1.2 Activation of the innate immune system as a "double-edged sword." Activation of innate immunity reflects a prerequisite for defense and repair of a septic focus, such as a perforated viscus. However, this may lead to collateral damage if spillover of inflammatory mediators or release of activated cells into the systemic circulation occurs.

Sepsis is defined and diagnosed by nonspecific alterations in temperature, heart and respiratory rate, and white cell count secondary to infection (Table 1.1) [4]. Unfortunately, in current clinical practice, neither the causative pathogen nor the specific cellular processes underlying deterioration of organ function that would be amenable to specific therapeutic intervention can be assessed in a way that would allow tailoring of anti-infective or immunomodulatory therapies to specific patient needs. This is particularly relevant given the pressing need to respond within the first few "golden" hours. These shortcomings regarding "point-of-care" diagnostics are in sharp contrast to the burgeoning development of sophisticated molecular tools and the improved molecular and cellular understanding of the pathogen-host interaction via specific receptors and signaling cascades [5, 6]. As stated by Nathan [2]: "it makes no sense to use twenty-first century technology to develop drugs targeted at specific infections whose diagnosis is delayed by nineteenth-century methods." Thus, development of innovative diagnostic tests and strategies are needed to optimize treatment strategies, not only in selecting the correct anti-infective agent but also modulating inflammatory and other responses to fundamentally improve outcomes in a "personalized" manner.

Table 1.1 Diagnostic criteria for the "systemic inflammatory response syndrome" (SIRS criteria)

The resulting diagnostic uncertainty regarding the causative pathogen reflects a central dilemma of intensive care physicians in treating life-threatening infections. On one hand, there is an important need to avoid delays in the initiation of appropriate antibiotics [7], yet this, in turn, triggers the overuse of "broad spectrum" antimicrobial agents creating a tremendous problem with multiresistant pathogens [8]. Likewise, many septic patients may already be in a state of overall immune suppression at the point of admission to intensive care, as anti-inflammatory systems are also activated in sepsis and these may outweigh the proinflammatory response. Introduction of an anti-inflammatory agent to such patients may arguably compromise the host even more.

1.2 Sepsis as a "Hidden Healthcare Disaster"

Sepsis arises from community-acquired infections but also, and more frequently, from healthcare-associated infections. It is a leading cause of morbidity and mortality worldwide. Its incidence is increasing, and the overall mortality is now in a similar range to that of myocardial infarction or stroke [9, 10]. This likely reflects changing demographics, with an aging population. In parallel, an ever-increasing number of invasive procedures, including those directly affecting the immune system, such as antineoplastic chemotherapy or organ transplantation, are performed in patients who would previously not have been considered for such procedures. As a consequence, the rate of hospitalization for sepsis in the United States increased from 221 per 100 000 population in 2001 to 377 per 100 000 in 2008 (Figure 1.3) [9]. A similar increase in the incidence of severe postoperative sepsis is also noted [11].

Figure 1.3 Sepsis - an underestimated and silently growing problem of modern healthcare: Because of multiple factors related to demographic changes, an increasing invasiveness of procedures in patients with inherent impaired immune function, and the advent of multidrug resistance in particular to Gram-negative pathogens, there is a silent but dramatic increase in the incidence of sepsis in healthcare systems across the world.

Sepsis has been called a "hidden public health disaster" [12]. Survivors carry an under-recognized risk of long-term cognitive and physical disability [13] and a more than twofold risk of dying over the next 5 years compared with appropriate controls [14]. The Center of Disease Control recently estimated that 15 billion dollars were spent on hospitalizations for sepsis alone in the United States and that inflation-adjusted aggregate costs for treating such patients increased annually by more than 10% [9].

1.3 Microorganisms and Types of Infection Triggering Sepsis

A recent global picture of infection and sepsis in ICUs worldwide is provided by the "Extended Prevalence of Infection in Intensive Care" (EPIC II) study. This reflects a 1-day, prospective, point prevalence study conducted on May 8, 2007, with subsequent follow-up [15]. Demographic, physiologic, bacteriologic, therapeutic, and outcome data were collected from approximately 14 000 patients in 1265 participating ICUs from 75 countries. These included 667 Western European ICUs, 210 Central and South American, 137 Asian, 97 Eastern European, 83 North American, 54 Oceanic, and 17 African. Sixty percent of participating ICUs were situated in university hospitals, 66% were mixed medical-surgical ICUs, and 94% had 24 h ICU physician coverage. On the study day, approximately half the patients were considered infected and 71% were receiving antibiotics. Infection was mostly of respiratory origin (66%), followed by abdomen (20%), bloodstream (15%), and renal tract/genitourinary system (14%). Microbiological cultures were positive in 70% of the patients with presumed infection, with 62% of positive isolates being Gram-negative organisms, 47% Gram-positive, and 19% fungi. The most common Gram-positive organism isolated was Staphylococcus aureus (20%), while the commonest Gram-negative organisms were Pseudomonas species (20%) and Escherichia coli (16%). Patients who had been in ICU for longer prior to the study day had higher rates of infection, especially with resistant and thus more difficult-to-treat pathogens, such as Staphylococci, Acinetobacter, Pseudomonas, and Candida species. Of note, ICU mortality (25% vs 11%) and hospital mortality (30% vs 15%) of infected patients was more than twice that of noninfected patients. Other, albeit smaller, surveys corroborate the EPIC II data and confirm the disease burden of infection in the critical care setting which increases with the duration of stay as well as with shifting patterns of microorganisms [16]. Since 2007, a substantial increase in difficult-to-treat infections has been observed. This is primarily attributable to multidrug-resistant Gram-negative bacteria, a proportion of which are virtually untreatable, such as some carbapenemase-producing Klebsiella strains...