Chapter 62 Nosocomial infection

Nosocomial or hospital-acquired infections are a major problem in hospitals, affecting up to 9% of inpatients at any one time. Intensive care units (ICUs) represent 2–10% of hospital beds, but are responsible for 25% of all nosocomial blood stream and pulmonary infections. In the European Prevalence of Infection in Intensive Care (EPIC) snapshot of prevalence the infection rate in ICU was 20.62%.¹ Nosocomial infection is, at least in theory, a preventable cause of morbidity and mortality (Table 62.1).

Table 62.1 Principles of diagnosis of nosocomial infections

• Diagnosis of infection usually requires the combination of both clinical findings and the results of diagnostic tests

• Clinical diagnosis of infection from direct observation at surgery, endoscopy or other diagnostic procedure is an acceptable criterion for an infection

• It must be hospital-acquired. There must be no evidence that the infection was present or incubating at the time of hospital admission. Infection acquired in hospital, but only evident after hospital discharge, also fulfils the criteria

• Usually no specific time during or after hospitalisation is given to determine whether an infection is nosocomial or community-acquired. Each infection is examined for evidence that links it to hospitalisation (this is a matter of controversy)

EPIDEMIOLOGY

The prevalence of nosocomial infection is reported as being between 3 and 12% in most institutions but varies considerably between different sites within each institution.² The vulnerability of the patient population, the nature of interventions and cross-infection are but three of many factors. This is seen clearly if one compares the range between ophthalmology and critical care – 0–23%.³

The site of infection varies with location so that, whereas the urinary tract and the chest are common throughout the hospital, within the ICU surgical wound infection, pneumonia and blood stream infection are far more common (8–12%).

The impact of nosocomial infection is impressive. Ventilator-associated pneumonia (VAP) is common, has significant morbidity with increased length of stay, associated costs and a twofold increase in mortality.⁴ It has been suggested that blood stream infections, surgical wound infections and nosocomial pneumonia result in 14, 12 and 13 attributable extra hospital days respectively.⁵ Catheter-related blood stream infection (CR-BSI) was also associated with major morbidity although, curiously, not necessarily mortality.⁶ The mortality rates directly due to these infections are hard to separate from the mortality attributed to the presenting severity of illness, which in its own right may have predisposed to infection. What is clear is that nosocomial infection is associated with increased mortality, and huge financial and resource costs.²

THE MECHANISMS INVOLVED IN NOSOCOMIAL INFECTION

A range of factors come together to enable nosocomial infection to occur. Some may be risk factors in their own right whereas other may simply represent an identifier of a sicker and therefore more vulnerable population (Table 62.2).

Table 62.2 Risk factors for nosocomial infection

Patient

Multiple or prolonged antibiotics

Blood transfusion

Environment

Changes in procedures or protocols

Multiple changes in staff; new staff

Poor aseptic practice – poor hand-washing

Patient-to-patient: busy, crowded unit, staff shortages

The organism

Resistance

Resilience in terms of survival

Formation of slime or ability to adhere

Pathogenicity

Prevalence

ENVIRONMENT

Local environmental pressures play their part. The combination of antibiotics, in particular multiple antibiotics, and cross-infection predisposes a vulnerable population to pseudomembranous colitis from Clostridium difficile toxin.⁸ Epidemiological patterns, such as the prevalence of Enterococcus faecalis as a common pathogen in the surgical population, may be linked to widespread cephalosporin usage. Much of the multiresistance problem probably originates from antibiotic pressures.⁹ Cross-infection is the biggest single problem in intensive care and transmission is by various means, but still the most common is by hands.¹⁰

ORGANISM

The host usually lives in synergistic or symbiotic tranquillity with a huge range of organisms (Table 62.3). Antibiotics suppress many normal organisms and allow the emergence and overgrowth of a usually insignificant organism or resistant organism of the same type. For example, an intrinsic organism such as Candida will flourish in the presence of broad-spectrum antibiotics and this overgrowth may result in symptomatic or even invasive candidiasis. Cephalosporin use may encourage the intrinsically resistant but quiescent enterococci to emerge as a dominant and problematic organism.

Table 62.3 Common commensals that may cause infection in a vulnerable host

Site	Common commensal organisms
Skin	Staphylococcus epidermidis, streptococci, Corynebacterium (diphtheroids), Candida
Throat	Streptococcus viridans, diphtheroids
Mouth	Streptococcus viridans, Moraxella catarrhalis, Actinomyces, spirochaetes
Respiratory tract	Streptococcus viridans, Moraxella, diphtheroids, micrococci
Vagina	Lactobacilli, diphtheroids, streptococci, yeast
Intestines	Bacteroides, anaerobic streptococci, Clostridium perfringens, Escherichia coli, Klebsiella, Proteus, enterococci

Extrinsic organisms may be introduced from the environment, from other patients, from staff or from surfaces. These may be organisms which are thriving in that environment because of local pressures (e.g. antibiotics), or from poor hygiene. Examples include Acinetobacter and, of course, meticillin-resistant Staphylococcus aureus (MRSA). On admission, patients will be carrying a range of organisms that have the potential to cause problems, but during their stay they are likely to acquire a new ecology from their surroundings. In a hospital that ecology may be quite hostile, with multiresistance being common.

The individual characteristics of the organism are important. These include their resilience in the local environment, the ease of transmission and the individual pathogenicity. This clearly interacts with the vulnerability of the host, as some usually innocuous organisms, such as Candida or Serratia marcescens, will only cause problems in vulnerable hosts whereas others, such as some strains of Staphylococcus aureus, Acinetobacter or Clostridium difficile, may be intrinsically more virulent.

THE ORGANISMS

A vast range of organisms can cause nosocomial infection (Table 62.4). It must be emphasised that each hospital and each ICU will have its own local ecology and knowing this ecology is important. Regional, national and international surveys give indications of general trends but this does not supplant local knowledge.

Table 62.4 Organisms responsible for the majority of nosocomial infections

Methicillin-resistant Staphylococcus aureus (MRSA)

Coagulase-negative Staphylococcus (CNS)

Enterococcus spp. (E. faecalis, E. faecium)

Pseudomonas aeruginosa

Acinetobacter baumanii

Stenotrophomonas maltophilia

Enterobacter spp.

Klebsiella spp.

Escherichia coli

Serratia marcescens

Proteus spp.

Candida spp. (C. albicans, C. glabrata, C. krusei)

Other organisms may be a problem in the severely immunocompromised, such as those with acquired immunodeficiency syndrome (AIDS: see Chapter 60)

Nosocomial infection is dynamic in that it is influenced by many environmental factors, the type of patient, type of surgery or illness, the antibiotic usage profile and many other variables. This dynamism is illustrated by the Gram-positive infections of the 1950s and 1960s, giving way to the Gram-negative infections of the 1970s and, while the multiresistant Gram-positive organisms are a major anxiety currently, they are already being superseded by superresistant organisms, such as Stenotrophomonas and Acinetobacter. The ease of transmission or development of resistance is a key factor in the current explosion in multiresistance.

The combination of sick patients and widespread use of potent antibiotics selects out problematic organisms and, as this epitomises intensive care practice, it is in ICU where multiresistance is common.

The organisms causing nosocomial infection may be endogenous or exogenous. Illness and antibiotics may both encourage the emergence and overgrowth of endogenous organisms that were normally suppressed and hence ecological change takes place in the skin, nasopharynx and gut. Alternatively the same factors influence colonisation with exogenous organisms from the environment. Cross-infection plays a significant role, as does the size of the local reservoir of exogenous organisms. The colonising organisms are well placed to invade or be introduced by invasive procedures, by devices or simply through areas of injury. Infection follows.

MULTIRESISTANT ORGANISMS

Many of the organisms that cause nosocomial infection are characterised by multiresistance. There are several mechanisms involved in resistance and in its spread. Enzymes, such as the β-lactamases, render a large array of antibiotics useless. Class 1 β-lactamase is effective against some β-lactam-containing antibiotics but extended-spectrum β-lactamases (ESBL), which incorporate enzymes, such as TEM-24, will produce cross-resistance to multiple classes of antibiotics, including fluoroquinolones and aminoglycosides. Resistance may be produced by a combination of mechanisms, such as in Pseudomonas aeruginosa, where the resistance is due to a combination of derepression of protein efflux systems, cephalosporinases and derepression of AmpC enzyme.

Resistance is acquired in a variety of ways. Mutation of any gene occurs at a rate of one cell in 10⁷ and, if this cell is then presented with antibiotics that it can survive, it will become a dominant cell, reproducing at a rate of 10⁹ overnight. An example of this might be the development of AmpC β-lactamase in Enterobacter, when patients are treated with third-generation cephalosporins. A similar example is the loss of porin OprD in P. aeruginosa in the presence of imipenem.

The big problem, particularly with ESBL, is that they can spread by plasmid transmission which is very rapid. The enzyme production is encoded chromosomally within an organism, and can then be transferred between bacteria by plasmids. Transposons transfer genes between plasmids. Examples of this include:

1 SHV-1 plasmid β-lactamase from Klebsiella

2 plasmid AmpC β-lactamases from Citrobacter

3 aminoglycoside-modifying enzymes from aminoglycoside-producing streptomycetes

The phenomenon of induction is also seen. This is the process whereby the presence of an antibiotic appears to ‘induce’ or speed up the production of the relevant enzyme so that the organism rapidly becomes resistant.

Staphylococcal resistance to meticillin occurs due to an altered penicillin-binding protein, which has low affinity for all β-lactam agents. It is linked to a MecA gene. This gene does not develop readily and spread of meticillin resistance is by vector transmission, not de novo production of resistance ⁷ (Table 62.5).

Table 62.5 The influence of extended-spectrum β-lactamases (ESBL) on resistance in Klebsiella

Antibiotics	ESBL-negative (% resistant)	ESBL-positive (% resistant)
Gentamicin	8	76
Amikacin	3	52
Ciprofloxacin	3	31
All the above	0	5

(Reproduced from Livermore DM, Yuan M. Antibiotic resistance and production of extended-spectrum beta-lactamases amongst Klebsiella spp. from intensive care units in Europe. J Antimicrob Chemother 1996; 38: 409–24.)