Classification of ICU InfectionsL.S

Classification of ICU Infections

L. S

, M. V

, H.K.F.

S

Introduction

Classifying infections is crucial in any infection surveillance program, in particu- lar in the intensive care unit (ICU). From the practical point of view, time cut-offs, generally 48 h, have been accepted to distinguish community and hospital- acquired infections from infections due to micro-organisms acquired during the patient’s stay on the ICU (i.e., ICU-acquired infections) [1]. However, many clini- cians have appreciated that an infection developing after 48 h of ICU stay, due to a micro-organism carried by the patient on admission to the ICU, can not be con- sidered as “true” ICU acquired. Obviously, this infection is nosocomial, i.e., the infection occurs in the ICU because the patient required intensive care treatment for her/his underlying disease associated with the immuno-paralysis. However, the causative micro-organism does not belong to the ICU microbial ecology, as the patient imported the micro-organism in her/his admission flora.

A new classification of ICU infections, based on knowledge of the patient’s carrier state, has been proposed [2]. This approach allows the distinction between imported, or primary, and secondary carriage of potentially pathogen- ic micro-organisms (PPMs), in addition to endogenous and exogenous infec- tions. The aim of this chapter is to compare the traditional approach with the novel concept of the use of the carrier state for classifying infection developing in critically ill patients requiring intensive care treatment.

Traditional and Novel Classifications of ICU Infections

The Traditional Approach

There are two standard means of traditionally classifying infections occurring

in the ICU: the Gram staining technique, which groups both micro-organisms

and infections into Gram-negative and Gram-positive categories, and the incuba- tion time, which distinguishes community from nosocomial infections (Table 1).

The in vitro staining method, described 120 years ago, is still used to distin- guish Gram-positive from Gram-negative bacteria, and to classify micro-organ- isms causing infection in the ICU. In the European prevalence study of infection in ICU (EPIC) [3], bacterial isolates were almost equally divided between Gram- positive and Gram-negative micro-organisms. However, there is no correlation between the Gram reaction of a particular micro-organism and its pathogenicity (see Chapter 4). For example, amongst five Gram-positive cocci present in the oropharynx of critically ill ICU patients, such as enterococci, coagulase-negative staphylococci (CNS), viridans streptococci, Staphylococcus aureus, and

lower airway infections, suggesting a different pathogenicity amongst Gram-pos- itive bacteria. Similarly, mortality is higher in ICU patients with a lower airway infection due to Pseudomonas aeruginosa than with Haemophilus influenzae, both aerobic Gram-negative bacilli (AGNB). Additionally, a worse outcome for septicemia due to AGNB has been reported compared with Gram-positive bacte- ria. However, bloodstream catheter-related infections due to CNS, which is asso- ciated with low mortality, are frequently included in these reports, artificially lowering the mortality due to Gram-positive bacteria. No difference in mortality was shown in a South African study between Gram-positive or Gram-negative community acquired septicemia due to high-level and potential pathogens [4].

We prefer to classify micro-organisms causing ICU infections according to their intrinsic pathogenicity index into low-level pathogens, high-level pathogens, and PPMs. Only high-level and potential pathogens cause mortality, whilst low-level pathogens only result in morbidity.

Studies on the prevalence of infections in ICU have included the usual defi- nition of hospital-acquired infections (i.e., nosocomial) issued by the Centers for Disease Control and Prevention (CDC) [5], “for an infection to be defined as

Table 1.Classification of ICU infection using the time criterion of 48 h

Type of infection Micro-organisms Timing Incidence

Community-acquired Within 48 h About 15%–50%^c

of ICU stay^b Hospital acquired Gram-positive

and/or Gram-negative^a

ICU acquired After 48 h About 50%–85%

of ICU stay

afor community, hospital and ICU-acquired infections

bonly for community and hospital-acquired infection

cthe percentage includes both community and hospital-acquired infections

nosocomial there must be no evidence that the infection was present or incu- bating at the time of hospital admission”. Based on this definition, the EPIC study, which enrolled 10,038 patient-cases with a total of 4,501 infected patients, distinguished each infection as one of the following (Table 1) [3]:

1. Community acquired: an infection occurring in the community and mani- fest on admission to the ICU

2. Hospital acquired: an infection manifest on admission to the ICU and deemed to be related to the present hospital admission

3. ICU acquired: an infection originating in the ICU, but not clinically manifest at the time of ICU admission.

This study showed that approximately 45% of enrolled patients were infect- ed; nearly half (46%) of these patients acquired their infection in the ICU. The vagueness of this definition has prompted investigators to adopt “incubation times” in order to improve the distinction between infections acquired in the community and/or hospital/ward from those acquired during the patient’s treatment on the ICU. Arbitrary time cut-offs varying between 24 h and 7 days [6–14] were chosen to distinguish ICU from non-ICU infections, because the CDC failed to specify a particular time cut-off [5]. The 48 h threshold has been applied in most epidemiological studies on infection rates in ICU, reflecting the firm assumption that all infections occurring after 2 days of ICU stay are noso- comial and due to micro-organisms transmitted via the hands of carers, and substantially magnifying the “ICU-acquired” infectious problem.

The Novel Approach

The traditional approach can now be challenged by the carrier state [2].

Carriage or carrier state exists when the same strain is isolated from at least two consecutive surveillance samples (e.g., throat and rectal swabs) from an ICU patient, at any concentration, over a period of at least 1 week [15]. Surveillance samples are samples obtained from body sites where PPMs are carried, i.e., the oropharynx and the digestive tract [15]. A surveillance set comprises throat and rectal swabs taken on admission and afterwards twice weekly (e.g., Monday and Thursday). Diagnostic or clinical samples are samples from internal organs that are normally sterile, such as lower airways, blood, bladder, and skin lesions;

they are only taken on clinical indication with the aim of microbiologically proving a diagnosis of inflammation, either generalized or local [15].

Knowledge of the carrier state, together with diagnostic cultures, allows the distinction between the three types of infection occurring in the ICU (Table 2):

1. Primary endogenous infections are the most-frequent infections in the ICU;

the incidence varies between 50% and 85%, depending on the population

studied and the degree of immunosuppression [16–21]. They are caused by

both normal and abnormal PPMs imported into the ICU by the patient in

the admission flora. These episodes of infection generally occur early, dur- ing the 1st week of ICU stay. The main infection problem in ventilated patients is lower airway infection occurring during the 1st week of ICU stay.

S. pneumoniae, H. influenzae, and S. aureus are the etiological agents in pre-

viously healthy individuals requiring intensive care following an acute event, such as (surgical) trauma, pancreatitis, acute hepatic failure, and burns. Abnormal hospital AGNB, such as Klebsiella spp., can cause primary endogenous infections in patients with previous chronic underlying disease, such as severe chronic obstructive pulmonary disease, following acute dete- rioration of the underlying disease. Adequate parenteral antibiotics given immediately on admission to the ICU reduce the incidence of primary endogenous infection [22].

2. Secondary endogenous infections are invariably caused by eight abnormal AGNB and methicillin-resistant S. aureus (MRSA), accounting for one-third of all ICU infections [16–21]. This type of infection, in general, occurs after 1 week on the ICU. These PPMs are first acquired in the oropharynx, and subsequently in the stomach and gut. The topical application of non- absorbable antimicrobials polymyxin E/tobramycin/amphotericin B has been shown to control secondary endogenous infection [23].

3. Exogenous infections (approximately 15%) are caused by abnormal hospital PPMs, and may occur at any time throughout the patient’s stay in the ICU.

Typical examples are Acinetobacter lower airway infection following the use of contaminated ventilation equipment, or cystitis caused by Serratia asso- ciated with urinometers, or a MRSA tracheobronchitis in a tracheostomized patient. Surveillance samples are negative for micro-organisms that readily appear in diagnostic samples. High levels of hygiene are required to control these infections [24].

According to this criterion, only secondary endogenous and exogenous infections are labeled ICU-acquired infections, whilst primary endogenous infections are considered to be imported infections. Figure 1 enables clinicians to classify infections based on knowledge of the carrier state.

Table 2.Three different types of infection due to 15 potentially pathogenic micro-organ- isms (PPMs)

Type of infection PPM Timing Incidence

Primary endogenous Normal/abnormal <1 week 55%

Secondary endogenous Abnormal >1 week 30%

Exogenous Abnormal Any time during ICU 15%

treatment

Evidence Behind the Time and the Carriage Classification of ICU Infections

There is no evidence that infections occurring on, or at a specific time after ICU admission, are attributable solely to micro-organisms transmitted via the hands of carers and, hence, acquired during the ICU stay [25]. It also still remains uncertain from the literature whether the given time cut-off refers to the num- ber of days on the ICU or the number of days following intubation. The failure of the CDC guidelines to specify a time cut-off has led to the introduction of arbitrary and different time cut-offs, and to the use of the type of micro-organ- ism causing the infections to distinguish between community, hospital-, and ICU-acquired infections. For example, H. influenzae is assumed to cause only community-acquired infections [26], P. aeruginosa must be nosocomial [16], and CNS are by definition the low-level pathogens causing catheter-related

YES NO

PPM carried in admission flora?

YES

Confirm the micro-organisms causing the infection by diagnostic or clinical

samples Detect the patient’s carrier

state on admission and twice weekly by surveillance

cultures

Combined information from surveillance (carriage) and diagnostic (infection)

samples

Is PPM causing infection carried by the patient in throat and/or gut?

PPM acquired during treatment on ICU leading to secondary or super-carriage

NO

Primary carriage

Exogenous infection Endogenous

infection

Primary endogenous infection

Secondary endogenous

or super-infection

Fig. 1.Flowchart for classifying infections in the ICU using knowledge of the carrier state (PPM potentially pathogenic microorganism)

infections [27]. Classifications based on time have been developed following the common experience of specific incubation times associated with highly patho- genic micro-organisms, both viral and bacterial. For example, the incubation time for varicella zoster and Salmonella typhimurium is 12 and 3 days, respec- tively [28]. These almost fixed incubation times are due to a high intrinsic path- ogenicity (or virulence) associated with varicella zoster virus and S. typhimuri-

influenza A virus infect healthy individuals. However, patients requiring inten- sive care develop infections with PPMs, including MRSA and AGNB, and with low-level pathogens such as CNS and enterococci, due to the severity of illness and associated immunosuppression [29]. The severity of illness rather than the virulence of the micro-organism will determine the time at which a potential pathogen or a low-level pathogen will cause infection [30, 31]. Clinicians, in extending the time cut-off, appreciated that infections developing in the first days after ICU admission have nothing to do with the ICU microbial ecology, and hence acknowledged that incubation time represents an inaccurate criteri- on for classifying infections in the critically ill. According to the pathogenesis of ICU-acquired infections, acquisition of a PPM is followed by carriage and overgrowth of that micro-organism before colonization and infection of an internal organ may occur. Undoubtedly, this process takes more than 2, 3, or 4 days to develop. Therefore, a low respiratory tract infection due to a PPM already carried in the throat and/or gut on admission and developing in a ven- tilated trauma patient after 3, 4, or even 10 days of ICU admission, can not be considered as ICU acquired.

In contrast, knowledge of the carrier state at the time of admission and throughout the ICU stay is indispensable in distinguishing infections due to

“imported” PPMs (i.e., primary endogenous) from infections due to bacteria acquired on the unit (i.e., secondary endogenous and exogenous). Only second- ary endogenous and exogenous infections are “true” ICU-acquired infections, as the origin of the causative bacteria is outside the ICU patient, the ICU envi- ronment. In the case of the secondary endogenous infections, the micro-organ- ism acquired on the unit goes through a digestive tract phase, but this does not apply to the exogenous infections.

Over the last 5 years, seven studies have prospectively evaluated the accura-

cy of the 48 h time cut-off using carriage as the gold standard (Table 3)

([16–21]; M. Viviani, personal communication). These studies included more

than 2,700 patients with more than 1,500 infection episodes. Five studies in

adult ICUs showed that 65%–80% of infections were classified as ICU acquired

by the use of the 48 h time cut-off ([16, 17, 19, 20]; M. Viviani, personal com-

munication). Conversely, when the carriage method was used, up to 50% of

those ICU-acquired infection episodes were re-classified as primary endoge-

nous. This figure was similar, or even higher, in the pediatric population [18, 20,

21]. Moreover, two cohort studies assessed the time cut-off that was most in line with the carrier state concept [17, 20]. A period ranging from 7 to 10 days (depending on the population studied) was found to identify more accurately ICU-acquired infections than the 48 h cut-off, although time was found to be a less-reliable method for identifying imported and ICU-acquired infections.

Impact of the Time and Carrier State Classification of ICU Infections

The main message of the traditionalists, who use a time cut-off of 48 h for clas- sifying infection, is that the ICU-acquired infectious problem is a huge early phenomenon involving about two-thirds (up to 85%) of all ICU infections. Their approach implies that most infections occurring on the ICU are nosocomial, due to micro-organisms transmitted via the hands of carers, except those established in the first 2 days. The 48 h time cut-off is also responsible for blaming staff for almost all infections occurring in the ICU and for initiating expensive transmis- sion investigations. Therefore, hand washing is highly recommended by influen-

Author No. of No. of Classification of infection episodes patients infection PE SE Exogenous ICU- Nosocomial

episodes acquired^* (48 h

cut-off)

Murray et al. [16] 21 12 6 (50) 6 (50) 0 6 (50) 9 (75)

Silvestri et al. [17] 117 74 44 (60) 17 (23) 13 (17) 30 (40) 59 (80) Petros et al. [18] 52 18 15 (85) 2 (10) 1 (5) 3 (15) 15 (83) de la Cal et al. [19] 56 37 21 (57) 14 (38) 2 (5) 16 (43) 30 (81) Silvestri et al. [20]

Adult 130 27 14 (52) 10 (37) 3 (11) 13 (48) 19 (70)

Pediatric 400 40 32 (80) 4 (10) 4 (10) 8 (20) 26 (65)

Sarginson et al. [21] 1,214 792 480 (61) 42 (5) 270 (34) 312 (39) 547 (69) Viviani M.^b 778 573 292(51) 173 (30) 108 (19) 281 (49) 379 (66) Total 2,795 1,573 904 (58) 268 (17) 401 (25) 669 (42) 705 (71)

aFor each study, the same episodes of infection are classified both with the carrier state con- cept and with the traditional 48 h cut-off. ICU-acquired, *total of secondary endogenous and exogenous infections based on the knowledge of the carrier state; nosocomial, the infection episodes of the previous columns are re-classified using the traditional 48 h time cut-off. Values in parentheses are percentages.^bViviani M., personal communication

tial authorities [32, 33] as the most important measure to control the exaggerat- ed nosocomial problem due to an overestimated level of transmission.

Community and hospital-acquired infections, which are present or incubating at the time of ICU admission, cannot be prevented by hand washing.

These concepts are in sharp contrast to the data from the seven previous studies. Table 3 and Figs. 2 and 3 show that more than 60% of all ICU infections are primary endogenous, i.e., due to micro-organisms not related to the ICU ecology, and develop during the 1st week of ICU stay. The remaining 40% are

“true” ICU-acquired infections and develop after 1 week. Hand washing cannot be expected to control primary endogenous infections because it fails to clear oropharyngeal and gastrointestinal carriage of PPMs present on arrival. Being inherently active solely on transmission, hand hygiene cannot reduce the major infection problem of primary endogenous infection, as transmission is not involved in this type of infection. Additionally, as an ex vivo maneuver, hand washing does not influence the immune status of the patient. [34]. Detection of primary endogenous infection as the major infection problem in the ICU avoids blaming health carers for misclassified infections after 48 h, for which they are not responsible, and prevents unnecessary expensive cross-infection investiga- tions. Finally, in strictly identifying the primary endogenous and the nosoco- mial problem of secondary endogenous and exogenous infections, the surveil- lance of both infection and carriage allows the intensivist to start with the appropriate prevention measures, including the selective decontamination of the digestive tract (SDD) [35–38].

Fig. 2.Histogram showing the three types of infections in the seven different studies (PE primary endogenous, SE secondary endogenous, EXO exogenous)(data from table 3)

Conclusion

Most ICU infections are due to micro-organisms that are carried by the patient on admission to the ICU. The difference in philosophy between the traditional- ists and those who advocate the carriage state method for classifying ICU infec- tions is that the former focus on the prevention of transmission of all micro- organisms via the hands of carers in order to control all Gram-positive and Gram-negative infections occurring after 2 days of ICU stay. However, we believe that ICU patients may benefit from an infection control program that includes surveillance of both carriage and infection. In detecting abnormal car- riage and overgrowth, surveillance cultures are indispensable for the identifica- tion of a subset of patients at high risk of infection. Awareness of carriage in long-stay patients can provide more insights into the epidemiology of infection.

The “true” nosocomial infection problem (i.e., secondary endogenous and exogenous infections) is easily and early detected. A monthly report of patients with only nosocomial infections may be useful, as the combination of second- ary endogenous and exogenous infections may highlight a transmission prob- lem in the ICU.

Fig. 3.ICU-acquired infections using the 48 h time cut-off versus the criterion of carriage (data from Table 3). The pie charts represent the ICU-acquired infection rate using the time and the carriage classification and mirror each other

Nosocomial Community ICU-acquired

Primary endogenous

58%

71%

42%

29%

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