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Antibiotic resistance in the ICU 

Antibiotic resistance in the ICU
Antibiotic resistance in the ICU
Oxford Textbook of Critical Care (2 ed.)

Jonathan Edgeworth


Key points

  • Most countries are documenting a steady increase in antimicrobial resistance amongst common bacterial pathogens found on the ICU.

  • The increase in antimicrobial resistance, particularly amongst Gram-negative bacteria compromises empiric therapy choices and can lead to selection of strains that are resistant to essentially all available antibiotics.

  • Infection prevention, control, and antimicrobial stewardship programmes aim to limit the selection and transmission of resistance on the ICU.

  • The ability of successful antibiotic-resistant clones to become pandemic necessitates a co-ordinated global response beyond local measures introduced on individual ICUs and health care institutions.

  • Advances in rapid diagnostics holds promise of providing identification and information on antimicrobial resistance of bacterial pathogens at the time of initial decision making in the treatment of septic patients on ICU.

Principles of pathogenesis and treatment of ICU-acquired infections

Infections dealt with on a general intensive care unit (ICU) can be defined as either community-associated or health care associated. Community-associated infections usually involve organisms with defined virulence factors conferring the ability to colonize surface epithelia, invade the host and then evade the immune system. In the pre-antibiotic era many were known to have a high mortality. Health care and more specifically ICU-associated infections usually involve organisms capable of colonization, but they require assistance with invasion through epithelial surfaces from a catheter, drain or knife, or the bypassing of other innate defences through insertion of endotracheal and urinary catheters. It is uncertain whether they use mechanisms to evade the immune system and the attributable mortality of ICU-acquired infections is hard to define because of the high background mortality associated with an ICU stay. Nevertheless ICU-patients frequently develop systemic inflammation that in the setting of a community-associated infection would indicate involvement of a virulent pathogen. Microbiological data does not become available for 2–3 days, and although biomarkers of systemic inflammation such as the white-blood cell count, C-reactive protein and procalcitonin are available within a few hours they have high sensitivity, but low specificity for predicting microbiologically confirmed infection. A decision to start antimicrobial therapy is therefore made empirically. Unfortunately, although bacteria commonly associated with ICU-acquired infections are remarkably similar worldwide (Table 289.1), they have higher intrinsic antimicrobial resistance than community bacteria and a frightening ability to acquire further resistance. Consequently, the selection of appropriate antibiotics for acutely unwell patient is challenging. There is usually a need to cover Gram-positive and Gram-negative bacteria (GNB) and sometimes fungi, particularly Candida spp. All three groups present problems, but it is particularly acute with GNB because there are such a large number of species and resistance elements. For this reason the main focus of this chapter will be on GNB. Many guidelines recommend two antibiotics active against GNB for treatment of ICU-acquired infections with de-escalation to a single antibiotic around day 3 when culture results become available. There is little evidence to guide length of therapy with practice ranging from 5 to 14 days [1]‌. Overall about half of ICU patients are judged to be infected at any one time and about 70% are receiving systemic antibiotics [2].

Table 289.1 A comparison between predominant bacteria causing community and hospital associated intensive care unit infections

Community-associated bacteria

Hospital/ICU associated bacteria

Gram positive

Staphylococcus aureus (MRSA*) (IR)

Staphylococcus aureus (MRSA) (IR, O)

Streptococcus pneumoniae

Coagulase negative Staphylococci

Group A Haemolytic Streptococcus

Enterococcus species (VRE) (O, IR)

Group B Haemolytic Streptococcus

Group C/G Haemolytic Streptococcus

Gram negative

Escherichia coli

Pseudomonas aeruginosa (O, AR)

Klebsiella spp.

Enterobacter spp. (O, AR)

N. meningitidis

Escherichia coli (AR)

Haemophilus spp.

Klebsiella spp. (O, AR)

Moraxella spp.

Morganella spp.

Legionella spp.

Serratia spp.

Proteus spp.

Acinetobacter baumanii (O, IR)

Citrobacter spp.

Stenotrophomonas spp. (IR)

Hafnia spp.

Other GNB

* Community MRSA has become more frequent in some parts of the world.

† There is a large number of different usually environmental GNB found sporadically and occasionally as small outbreaks in ICU that separately can be considered rare but collectively can be identified on about 5–10% of ICU patients (e.g. Chryseomonas, Commomonas. Ochrobacter, Elizabethkingae).

O, frequently reported to cause outbreaks; IR, high level of intrinsic antibiotic resistance; AR, frequent additional clinically relevant acquired resistance.

Main resistant organisms and resistance mechanisms

A comprehensive description of antimicrobial resistance genes and mechanisms has been recently reviewed elsewhere [3]‌. Many common ICU bacteria such as P. aeruginosa, Enterobacter spp., MRSA and Enterococcus faecium have intrinsic, but predictable resistance to antibiotics commonly used for community infections. Thus empiric therapy for ICU-acquired infections usually comprises one or more antibiotics from 6 main classes, comprising aminoglocosides, fluoroquinolones, third generation cephalosporins, aminopenicillins, carbapenems, and polymixins that have activity against Gram-negative bacteria, with the addition of a glycopeptide or oxazolidinone if MRSA is considered a likely cause. The choice of antibiotic(s) with activity against GNB is usually based on local levels of resistance to each agent and is made challenging by a number of emerging trends including:

  • Intercontinental spread of plasmids with extended spectrum β‎-lactamases (ESBL) particularly CTX-M, active against cephalosporins and aminopenicillins, and often linked fluoroquinolone and aminoglycoside resistance elements that are found in Klebsiella spp., E. coli, and other Enterobacteriaciae.

  • Development of resistance in P. aeruginosa to many antibiotic classes under selective pressure of antibiotic use on ICU.

  • Endemic colonization of ICUs with organisms such as A. baumanii that can be resistant to all commonly used antibiotics.

  • Increasing carbapenem resistance due to a variety of mechanisms commonly manifesting as either:

    • P. aeruginosa outbreaks.

    • Emergence of intrinsically resistant bacteria, such as S. maltophilia.

    • Most importantly, selection of numerous transferable plasmids encoding carbapenemases (eg KPC, IMP, OXA 48 and NDM) within enterobacteriaceae particularly E. coli and Klebsiella that have the potential for pandemic spread [4]‌.

Together this creates a high degree of uncertainty selecting empiric GNB therapy in ICU patients. There has been an increasing reliance on carbapenems in many ICUs over the past 5–10 years even as first line, but the emergence of resistance compromises this choice and is leading to use of older agents such as colistin that have more side-effects [5]‌.

Main factors increasing the burden of antimicrobial resistance on ICU

Antimicrobial resistance increases on ICU through importation, patient-to-patient transmission, selection in an individual, horizontal gene transfer within and between bacterial species and induction of new resistance (Fig. 289.1) [6]‌. The relative importance of each pathway varies between species and antibiotic resistance mechanism. Two main factors influence these pathways: antimicrobial use and health care practices.

Fig. 289.1 Control of Gram-negative resistance is much more complicated: multiple species, resistance mechanisms and potential routes of transmission.

Fig. 289.1 Control of Gram-negative resistance is much more complicated: multiple species, resistance mechanisms and potential routes of transmission.

R, resistant; S, sensitive.

Importation of resistance on patients (and to a lesser extent staff) reflects antimicrobial use in the community and the result of previous health care contacts. In addition, patients transferred out of ICU often have a prolonged stay on general wards where they may transmit resistance to other patients who then get admitted to ICU. Some patients have multiple admissions to hospital or the ICU providing many opportunities for increasing imported resistance.

Transfer of resistant organisms from patient to patient predominantly occurs via contaminated health care workers hands either directly from patient-to-patient or via inanimate objects. Antibiotic use may also influence transmission although this is likely to be complex given the potentially opposing effects of the many prescribed antibiotics [7]‌.

Induction of resistance due to selection of new mutations during antimicrobial therapy may be a particular problem in units with high antimicrobial consumption. Fluoroquinolones are reported to be associated with induction of resistance in enterobacteriaciae and P. aeruginosa during therapy. There is emerging evidence for outbreaks of resistance with transfer of mobile resistance elements both within and between species [8]‌, although the frequency, risk factors, and mechanisms of limiting such resistance are unclear.

Outbreaks of resistance

An outbreak can be defined as a period of increased incidence above an expected background The literature is dominated by reports of species outbreaks with resistant organisms such MRSA, Acinetobacter and MDR-Klebsiella that presumably drew significant clinical attention at that time. It is not clear what the total burden of outbreaks is on ICU and thereby derive general conclusions about risk factors and dissemination routes [9]‌. Outbreaks are often identified by a member of the health care team, although there are resistance outbreak detection tools that provide a more objective surveillance method [10,11]. It will be interesting to explore what might underlie the difference between large ‘outbreaks’ that reach clinical attention, and small clusters of largely sub-clinical and presumably self-terminating transmission clusters. Large outbreaks are often attributed to lapses in infection control practice, a patient or staff ‘superspreader’ or an environmental reservoir although some bacteria may be more adapted to spread better on the ICU [12].

Preventing the emergence and transmission of resistance on the intensive care unit

There are two main intervention programmes targeting a reduction in antimicrobial resistance: infection prevention and control (IPc), and antimicrobial stewardship.

An ICU infection prevention and control programme

An effective ICU IPc programme includes universal and targeted measures [13]. Universal measures that can be implemented in all ICUs include universal hand hygiene, environmental cleaning, and a training programme for staff that includes aseptic techniques required for good nursing and medical care. Success of these behavioural and operational practices benefits from a combination of education, training, and audit with clear accountability from ‘board to ward’ with consequences for poor performance. IPC has been transformed in many countries over the past few years by political, media, and public campaigns, demanding reductions in health care-associated infections to improve patient safety in hospitals.

Targeted components of an IPc programme comprise isolation and decolonization of patients carrying specific resistant organisms. Isolation can be used broadly to define any physical or distance barrier placed around a colonized patient and ranges from gloves and aprons for staff (contact precautions), patient cohorting or side-room isolation with or without staff cohorting, and use of an isolation ward. An additional component of a targeted IPc programme is collection of active surveillance cultures (ASC) to rapidly identify colonized patients and implement infection control interventions. Organisms most frequently screened are MRSA, VRE, and certain MDR-GNBs. A key attribute of a screening programme is the speed of returning results for action. Conventional culture often takes 3–4 days, which could be close to the median length of stay, such that results are delivered as the patient leaves. More rapid laboratory culture and molecular techniques can bring the turnaround time to same day or next day, and some point of care tests are being evaluated for organisms such as MRSA and C. difficile that provide results within a few hours. The effectiveness and cost-effectiveness of ASC programmes remains unclear.

Decolonization of patients with known resistant species is the other common targeted intervention, introduced to reduce both infections in the individual patient and transmission to others. With MRSA, decolonization involves use of surface antiseptics such as chlorhexidine and nasal mupirocin. In healthy patients, this has a reasonable chance of effecting MRSA eradication; however, in the ICU setting where patients have multiple skin breaches eradication is not considered achievable and the IPc goal is suppression at surfaces to reduce the bacterial load available to contaminate health care worker hands. The use of systemic antibiotics to further suppress the bacterial load of MRSA is not generally recommended on ICU. There is evidence that surface agents such as chlorhexidine may also suppress VRE at skin sites leading to a reduction in transmission. Skin antiseptics probably have little effect on MDR-GNB transmission, given that they predominantly colonize the gut and respiratory tract. There is evidence that enteral components of the selective digestive decontamination protocol, which includes neomycin and polymixin, suppress GNBs including MDR-GNB carriage in the gut, colonization of the respiratory tract and potentially transmission [14], although it’s use has not become widespread in part due to concerns about emergence of resistance.

Although targeted decolonization is an accepted intervention for known MRSA carriers, there is a growing practice of using surface antiseptics such as chlorhexidine for all patients on ICU from admission [15]. Thus, although a distinction is generally made between universal and targeted components of an infection control programme, given that all ICU patients are at high risk of acquiring or carrying resistant organisms universal contact precautions and surface antiseptic decolonization is currently implemented in some ICUs. Although, this may be feasible in some settings, the lack of evidence to support effectiveness and cost-effectiveness of universal measures leads to a wide variation in practice [16].

Antimicrobial stewardship programme

A second approach to controlling antimicrobial resistance on ICU is the reduction of inappropriate antimicrobial prescribing through implementation of a stewardship programme [17]. The principle is that although international and local guidelines are usually in place recommending choice and duration of antibiotic therapy for ICU-acquired sepsis, there is huge scope for variation in practice within and between units. This variation is perhaps compounded by recognition that the grade of evidence supporting treatment guidelines is mostly poor. Stewardship therefore aims to support decision-making and adherence to generally acceptable guidelines endorsed by local stakeholders. Measures include introducing restriction or pre-approval for certain antimicrobials; regular advice provided by a visiting infection specialist to the attending team, on the need, choice, and duration of antibiotics in individual patients; formal review of therapy around day three to implement de-escalation, particularly if combination empiric GNB-therapy is used; and introduction of computer assisted decision making or automatic stop dates. Finally, studies have investigated whether some guidelines are more associated with resistance than others, comparing heavy reliance on a limited range of antibiotics, regular cycling from one class to another or continuous mixing [18,19].

New interventions to help control antimicrobial resistance

A number of new technologies are on the horizon with the potential to provide more and faster clinically-useful microbiological and epidemiological information, which should improve both treatment of sepsis and infection control practice leading to a control of antimicrobial resistance on ICU [20]. Multiplex PCR technologies are in development that can identify organisms in clinical samples within a few hours. Such information could be used to deliver more appropriate empiric therapy for those with positive samples and in theory the withholding of antibiotics in those with negative samples. High throughput and rapid (same day) whole pathogen genome sequencing (WPGS) technologies are also being developed that may provide genotypic prediction of antimicrobial resistance phenotype and help with early detection of outbreaks. It is still unclear how long these disruptive technologies will take to enter routine practice, whether they will be used to guide both infection control and early therapy decisions, and whether they will save lives and resources and reduce resistance. There also remains an underlying need for better evidence on when to start antibiotics in ICU patients and how long to treat for. It is generally accepted that antibiotics are overused in ICU, but hard to strike a balance at the bedside between the needs of the individual patient for appropriate empiric therapy and the needs of society to prevent emergence of resistance. Hopefully a combination of new evidence from multi-centre randomized studies, including those that evaluating rapid diagnostics will meet this important challenge.


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