Multidrug Resistance in Severe Sepsis and Septic Shock

Abstract

Severe sepsis and septic shock are major challenges in intensive care units (ICU) and major healthcare problems, affecting millions of people around the world each year (1). Multiple definitions and terminologies are currently in use for sepsis, septic shock, and organ dysfunction, leading to discrepancies in reported incidence and observed mortality. Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (2). Pathophysiology of sepsis is complex processes that encompass interaction of pro-inflammatory and anti-inflammatory cytokines, humoral, cellular, and circulatory involvement resulting from dysregulation of the immune response to infection and associated with hematological, hemodynamic and metabolic disturbances leading to diffuse endothelial disruption, vascular permeability, vasodilation, and thrombosis of end-organ capillaries. Endothelial damage itself can further activate inflammatory and coagulation cascades, creating a positive feedback loop and leading to further endothelial and end-organ damage (3). Antibiotic resistance has been recognised ever since antibiotics were first discovered. There has been a recent push to increase awareness in the wider community to highlight this major threat to global health. World Health Day 2011 had the theme ‘antimicrobial resistance: no action today and no cure tomorrow.’(4). Multidrug resistance (MDR) bacteria represented 36 % of microorganisms identified in patients with confirmed infection (5). The main risk factors for resistance are prior exposure to antibiotics, prolonged hospital and ICU length of stay (LOS), invasive devices, comorbidities and local epidemiology (6). Multidrug resistance (MDR) is a well-known risk factor for mortality in critically ill patients with severe infections (7). Bacteria can be intrinsically resistant to certain antibiotics but can also acquire resistance to antibiotics via mutations in chromosomal genes and by horizontal gene transfer (8). Regardless of the complexity of these issues, there are basic biological mechanisms employed by bacteria to confer phenotypic resistance to antibiotics. Many resistant strains of bacteria have more than one mechanism of resistance. The Four main biochemical mechanisms of antibiotic resistance are altered target site, decreased antimicrobial uptake, ‘bypass’ pathways and enzymatic inactivation or modification (4). Management of septic shock should be according to Surviving Sepsis Campaign care bundles and Early goal-directed therapy (EGDT) with early antibiotics and source control (9). Preventive and therapeutic strategies of highly resistant bacteria include infection control measures, antibiotic stewardship, adequate prompt therapy for adequate duration and new therapeutic approaches like nebulized antibiotics in lung infections (6). Infection control is the first line in the prevention of infection dissemination by eliminating the means of transmission.Infection control measures combines the systematic use of standard precautions (hand hygiene, gloves, gowns, eye protection) and transmission- based precautions (contact, droplet, airborne) (10). The concept of antibiotic stewardship evolved to individualize prescriptions by the introduction of new concepts such as avoiding unnecessary administration of broad-spectrum antibiotics and systematic de-escalation(11). Combination therapy should be recommended only in patients with severe sepsis and when an infection with a resistant organism is likely. De-escalation to an effective monotherapy should be considered when an antibiogram is available (6). The proplem of the lack of new antibiotics, especially for MDR organisms has been highlighted by numerous agencies and professional societies. The Infectious Diseases Society of America (IDSA) supported a program, called ‘‘the 10× ́́ 20 Initiative’’, with the aim to develop ten new systemic antibacterial drugs by 2020 through the discovery of new drug classes or new molecules from already existing classes of antibiotics (12).