Thirty per cent of patients will become febrile, while up to 90% of patients with sepsis will experience fever, during a stay in the intensive care unit (ICU). Fever in critically ill patients may be of infective, non-infective, or mixed origin. The confirmation of the source of fever is often difficult which leads to a diagnostic dilemma and a difficult decision (to treat or not to treat) often resulting in a variability of treatment response from the medical and nursing staff.

The Society of Critical Care Medicine practice parameters define fever in the ICU as a (core) temperature above 38.3°C. The condition is caused by an imbalance between heat production and heat loss. In the clinical context, excessive heat generation is much more common than defective heat loss. The resulting disturbance may be transient and/or trivial or it may portend serious illness.

This module focuses on the differential diagnosis of fever rather than on the antimicrobial treatment of infection.

Antimicrobial agents work by killing or preventing the growth of a microorganism whilst having little or no impact on the host. Antimicrobials include agents that act against all types of microorganisms: bacteria (anti-bacterial), viruses (anti-viral), fungi (anti-fungal) and protozoa (antiprotozoal). Dosing regimens of antimicrobials should be optimised to prevent or minimise resistance. Suboptimal dosing has been attributed to poorer clinical outcomes and cure rates, as well as increasing the risk of morbidity and mortality.  

Pharmacokinetics (PK) is the study of the time course of drug absorption, distribution, metabolism and elimination i.e. what the body does to a drug. Pharmacodynamics (PD) is the study of the relationship between drug concentration at the site of action and the resulting effect i.e. what the drug does to the body. 

Target PK* and PD* indices are crucial to achieving maximal antibiotic activity and effective treatment of infection. However, adequate antimicrobial dosing to achieve PK/PD targets remains a challenge. The administered drug doses are frequently obtained from data from healthy individuals and often do not account for PK/PD differences in different patient populations, such as septic patients. Thus, optimising antimicrobial dosing regimens requires robust knowledge of the pharmacokinetics and pharmacodynamics of the antimicrobial agent. 

It should be noted that PK/PD principles relate to all drugs but for the purpose of this eModule the focus being on antimicrobial agents.  

Since the introduction of antibiotics in the 1930s, illness and death from infectious diseases have declined tremendously. As an example, estimates using historical data suggest a number needed to treat (NNT) of 5 for saving a life in patients with community acquired pneumonia. This shows that antibiotics are of vital importance for human health care.

Severe infections are most prevalent and antibiotic use is most abundant in intensive care units (ICUs) where on average 70% of patients receive an antibiotic (Vincent et al. 2009). These circumstances demand that intensivists have a profound and up-to-date knowledge of all aspects of infection management in critically ill patients. This includes familiarity with diagnostic strategies, criteria on when and how to start antibiotic treatment, how to assure that the right dose and right antibiotic is given and when to de-escalate and stop antimicrobial therapy when it is not necessary anymore.

Unfortunately, over-treatment is common in critically ill patients and as much as half of the antibiotics prescribed to patients in the ICU have been estimated to be excessive. This can be due to several reasons, e.g. antibiotics are started in a patient without clear signs of infection, prescription of more than one antibiotic when combination therapy is not necessary or a duration of treatment that is unnecessarily long. The extensive and often inappropriate use of antibiotics inevitably has led to the development of microorganisms resistant to commonly used antibiotics. In addition to high levels of antibiotic use, multiple facilitators for the development of resistance are present in the ICU setting, including loss of physiological barriers and a high transmission risk (Schouten and De Waele 2017). The rates of resistance are quite variable in different regions of the world. The website of the European Centre for Disease Prevention and Control (ECDC) offers an insight into the distribution of multidrug resistance in Europe. Furthermore, local resistance data on the level of individual hospitals are usually available to clinicians and have an influence on the choice of antibiotics used in empirical therapy.

Healthcare-associated (nosocomial) infection and the emergence of resistant micro-organisms are major concerns for healthcare systems worldwide. 

Infection is a major cause of critical illness and infection acquired in the ICU prolongs ICU stay and increases mortality. Critically ill patients are also highly susceptible to nosocomial infections. Frequent use of antibiotics contributes to selection pressure for resistant organisms, which may then become transmitted to other patients, wards and even hospital areas following patient discharge. A proper understanding of the mechanisms and means of prevention of nosocomial infection is therefore a basic component in the training and daily professional practice of all intensivists. 

This module reviews the scale of the problem of antimicrobial resistance and nosocomial infection, the methods for recognising and detecting infection, and their management and prevention. The module will focus on the acutely unwell patient primarily in the context of critical care, but the general principles are applicable throughout the healthcare system. It will also place particular emphasis on antibiotic stewardship and the responsibilities of both individuals and organisations in preventing these conditions which cause significant morbidity and mortality.