Download Classification of Micro-Organisms According to Their Pathogenicity

Chapter 4
Classification of Micro-Organisms According to
Their Pathogenicity
M.A. DE LA CAL, E. CERDÀ, A. ABELLA, P. GARCIA-HIERRO
Introduction
Isenberg wrote in 1988: “A modern clinical microbiologist who asks what is a
pathogen and what is meant by virulence will meet with derision and probably
be declared heretic, bereft of his or her senses” [1]. He expressed the difficulties
in defining the concepts of pathogenicity and virulence that have changed, and
are still changing, with the growing number of infectious diseases in the hospital setting and in the immunocompromised host.
It is accepted that infection is the result of the interaction between the host,
the micro-organism, and the environment. Pathogenicity (Table 1) is not only
an intrinsic quality of micro-organisms but the consequence of some properties of the micro-organisms and the host. For example, coagulase-negative
staphylococcus has been considered an avirulent, opportunistic organism and
not a true pathogen [5], but the increasing number of bacteremias due to this
organism in the past decades has emphasized its pathogenicity and virulence.
The ability of coagulase-negative staphylococcus to induce disease increases
when a patient’s defence mechanisms are altered. Freeman et al. [6] emphasized
that the fivefold increase of coagulase-negative staphylococcus bacteremia
found in a neonatal care unit from 1975 to 1982 was mainly attributed to an
increase in the number of children with a birth weight less than 1,000 g. Thus,
the separation of pathogenicity, defence mechanisms, and type of infection is
only justified for didactic reasons. Some terms routinely used by physicians
working in intensive care units (ICUs) describe many aspects involved in pathogenicity.
1. Intrinsic characteristics of bacteria, i.e., Gram’s stain, aerobic-anaerobic
requirements for growth, antibiotic sensitivity-resistance patterns.
2. Quantitative criteria for defining some infections, i.e., pneumonia associated with mechanical ventilation or urinary tract infection. For instance, the
probability of having pneumonia is higher if the quantitative culture of a
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M.A. de la Cal, E. Cerdà, A. Abella, P. Garcia-Hierro
Table 1. Glossary of terms [2, 3]
Pathogenicity: The ability of micro-organisms to induce disease, which may be assessed by
disease-carriage ratios
Virulencea: The severity of the disease induced by micro-organisms. In epidemiological
studies virulence may be assessed by mortality or morbidity rates and the degree of communicability
Reservoir: The place where the organism maintains its presence, metabolizes, and replicates
Source: The place from which the infectious agent passes to the host. In some cases the
reservoir and the source are the same, but not always
Infection: A microbiologically proven clinical diagnosis of inflammation
Carriageb: Permanent (minimally 1 week) presence of the same strain in any concentration
in body sites normally not sterile (oropharynx, external nares, gut, vagina, skin)
Abnormal carrier state: The abnormal carrier state exists when the isolated micro-organisms is not a constituent of normal flora (i.e., enterobacterial or pseudomonal strains) [3]
Colonizationb: The presence of micro-organisms in an internal organ that is normally sterile (e.g., lower airways, bladder). The diagnostic sample yields less than a predetermined
level of cfu/ml of diagnostic sample [3]
aSome
authors [4] consider virulence as a synonym of pathogenicity
authors [2] define colonization as the permanent presence of a micro-organism in
or on a host without clinical expression. Carrier state is the condition of an individual colonized with a specific organism. These definitions do not take the sterility of colonized sites
in normal subjects into consideration
bSome
protected brush catheter sample yields 104 colony forming units (cfu)
instead of 103 cfu. Even the significance of the quantitative culture is different if the patient is neutropenic. These criteria are related to the classic concept of infective dose, which is the estimated dose of an agent necessary to
cause infection.
3. Sites of isolation when evaluating the clinical significance of a culture. For
instance, Staphylococcus aureus may colonize the external nares without any
evidence of disease but its presence in a fresh surgical wound may indicate
colonization or infection.
4. “Community” versus “hospital” versus ICU-acquired flora, which recognizes
that the relationship between the different species, the host, and the environment induces changes in the microbial habitat.
5. Carriage, colonization, and infection, which defines some possible host
states according to the significance of the presence of micro-organisms in
different organs.
Classification of Micro-Organisms According to Their Pathogenicity
51
6. Exogenous, primary endogenous, and secondary endogenous infections,
which describe a pathogenetic model based on some epidemiological criteria.
In this chapter we will address the concept of pathogenicity and the epidemiological aspects of micro-organisms in clinical practice.
The Magnitude of the Problem
The surveillance of micro-organisms in the oropharynx, respiratory and digestive tracts in ICU patients has provided an essential basis for our present understanding of infectious diseases in the ICU:
- Patients’ flora change after hospital admission and this process is time
dependent [7–9].
- In a high percentage of cases, from 70% to 100% [7, 8, 10], infections were
preceded by oropharyngeal or gut carriage with the same potentially pathogenic micro-organism (PPM).
- Digestive tract is usually the reservoir of antibiotic-resistant strains.
- Different micro-organisms found in the same patient show different abilities
to induce infection, i.e., they have a different pathogenicity.
Those observations imply two questions: Where is the flora and which types
of flora can be differentiated on an epidemiological basis?
The Habitat
It is estimated that the human body consists of approximately 1013 cells and
hosts 1014–1015 individual micro-organisms [1]. These micro-organisms can be
divided into two groups: those that usually remain constant in their normal
habitat (indigenous flora) and those that are accidentally acquired and after
their adherence to epithelial or mucosal surfaces have to compete with other
micro-organisms and host defences. The final outcome could be clearance or
colonization of the new organisms.
Body areas that usually harbor micro-organisms (Tables 2, 3) are skin,
mouth, nasopharynx, oropharynx and tonsils, large intestine and lower ileum,
external genitalia, anterior urethra, vagina, skin, and external ear. Nevertheless,
the various anatomical sites suitable for microbiological habitats display overlapping boundaries and are subject to variation. Temporary habitats include
larynx, trachea, bronchi, accessory nasal sinuses, esophagus, stomach and upper
portions of the small intestine, and distal areas of the male and female genital
organs [12], and permanent colonization is often found in patients with some
risks factors, i.e., chronic bronchitis [13].
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M.A. de la Cal, E. Cerdà, A. Abella, P. Garcia-Hierro
Table 2. Micro-organisms commonly found in healthy human body surfaces [11]
Surface
Micro-organism
Frequency of isolation
Skin
Staphylococcus epidermidis
Diphtheroids
Staphylococcus aureus
Streptococcus spp.
Acinetobacter spp.
Enterobacteriaceae
4+
3+
2+
+
±
±
Mouth and throat
Anaerobic Gram-negative spp.
Anaerobic cocci
Streptococcus viridans
Streptococcus pneumoniae
Streptococcus pyogenes
Staphylococcus epidermidis
Neisseria meningitidis
Haemophilus spp.
Enterobacteriaceae
Candida spp.
4+
+
4+
2+
+
4+
+
+
±
2+
Nose
Staphylococcus epidermidis
Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes
Haemophilus spp.
4+
2+
+
+
+
Large intestine (95% or more of Anaerobic Gram-negative spp.
species are obligate anaerobes) Anaerobic Gram-positive spp.
E. coli
Klebsiella sp
Proteus spp.
Enterococcus spp.
Group B streptococci
Clostridium spp.
Pseudomonas spp.
Acinetobacter spp.
Staphylococcus epidermidis
Staphylococcus aureus
Candida spp.
4+
4+
4+
3+
3+
3+
+
3+
+
+
+
+
+
External genitalia
and anterior urethra
4+
+
+
±
“Skin flora”
Gram-negative anaerobic spp.
Enterococcus spp.
Enterobacteriaceae
cont. ➝
53
Classification of Micro-Organisms According to Their Pathogenicity
Table 2. cont.
Surface
Micro-organism
Frequency of isolation
Vagina
Lactobacillus spp.
Gram-negative anaerobic spp.
Enterococcus spp.
Enterobacteriaceae
Acinetobacter spp.
Staphylococcus epidermidis
Candida spp.
4+
2+
3+
1+
±
1+
1+
Relative frequency of isolation: 4+ almost always present; 3+ usually present; 2+ frequently present; + occasionally present; ± rarely present
Table 3. Quantitative cultures of healthy human surfaces [3]
Surface
Micro-organism
Skin (per cm)
Staphylococcus epidermidis
Anaerobes (Propionibacterium acnes)
Mouth and throat
(per ml of saliva)
Anaerobic micro-organisms
Streptococcus viridans
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Large intestine
(per g of feces)
Anaerobic spp.
E. coli
Enterococcus
Staphylococcus aureus
Candida spp.
Vagina
Aerobic spp.
(per ml of vaginal fluid) Anaerobic spp.
% Carriers
cfu
100
100
105
103
100
100
30–60
30–80
5
30
108
106
103–105
103–105
103–105
103
100
100
100
30
30
1012
103–106
103–106
103–105
103–105
100
100
108
107
The Flora
The indigenous flora is very dynamic and reflects changes induced by environmental settings, medical treatments, and host and microbial characteristics. It
is well accepted that normal subjects have a flora called normal indigenous
flora (Tables 2, 3) that represents the equilibrium reached between the normal
hosts and the organisms. The quantitative estimation of different micro-organisms found in human body surfaces helps us to understand the pathogenicity
because it is often obvious that predominantly isolated micro-organisms rarely
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M.A. de la Cal, E. Cerdà, A. Abella, P. Garcia-Hierro
induce disease. Anaerobes are a good example of organisms of low pathogenicity. They represent the highest percentage of micro-organisms isolated per surface area but they are only involved in a small proportion of infections.
Surveillance cultures performed in patients after hospital or ICU admission
[7–9] have demonstrated that flora changes over time. The carriage of aerobic
Gram-negative bacilli (AGNB) Pseudomonas spp., Klebsiella spp., Enterobacter
spp., Acinetobacter spp., Serratia spp., Morganella spp. and yeasts Candida spp.
increases. This process of acquisition of new organisms is time dependent. For
example, Kerver et al. [7] studied 39 intubated patients admitted to the ICU for
more than 5 days, obtaining samples three times a week from the oropharynx,
tracheal aspirate, urine, and feces. The prevalence of AGNB in the oropharyngeal cavity on admission was 23% and increased to 80% after 10 days. Similar
figures were found for yeasts. In feces, the prevalence of AGNB other than E. coli
was 20% and reached 79% on day 15. Yeasts were found in 13% of rectal swabs
on admission and in 61% of samples on day 15. In 75.6% of infections, the same
PPM was found in previous surveillance cultures [10].
This new flora comes into the human body from different animate (mostly
patients and uncommonly health personnel) or inanimate (e.g., food, furniture)
sources through different vehicles (e.g., hands, respiratory equipment). After
being introduced, the new organisms adhere to surfaces and have to compete
with pre-existing flora and host defence barriers before a permanent carriage
state is achieved. Apart from the severity of the underlying disease, parenteral
antibiotic administration is the main mechanism that favors the acquisition of
hospital flora through selective pressure exerted against indigenous flora [14].
The boundaries between normal, community, and hospital flora are not
always strict. Some groups of patients admitted to the hospital carry organisms,
usually constituents of hospital flora. Alcoholism, diabetes, and chronic bronchitis have been regarded as risk factors for carrying aerobic Gram-negative
bacilli [13, 15] in the oropharynx and in the tracheobronchial tree, respectively.
Classification of Micro-Organisms According to their
Pathogenicity
Leonard et al. [16] attempted to quantitatively estimate intrinsic pathogenicity
in a population of 40 infants admitted for at least 5 days to a neonatal surgical
unit. The intrinsic pathogenicity index (IPI) for a y species was defined as:
Number of patients infected by y
IPIy = ––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
Number of patients carrying y in throat/rectum
Classification of Micro-Organisms According to Their Pathogenicity
55
The range of this index is 0–1. The highest IPI found was for Pseudomonas
spp (0.38). Other potential pathogens isolated had an IPI of less than 0.1
(Enterobacter spp. 0.08, S. aureus 0.06, Klebsiella spp. 0.05, E. coli 0.05, S. epidermidis 0.03, and Enterococcus spp. 0). This index provides useful information
about the relative pathogenicity of different micro-organisms in a specific population and could be used to design antibiotic policies, both prophylactic and
therapeutic, in selected groups of patients in which microbiological surveillance could be indicated (e.g., burns, severe trauma patients).
There are inherent limitations related to the small number of studied
patients and the small number of infections (i.e., S. aureus 1 infection over 17
colonizations), which can give an unreliable estimation of the IPI. Furthermore,
the authors suggested that the results should be interpreted taking into account
technical aspects (definitions used, sites chosen for surveillance, microbiological techniques, interpretation of results) and population characteristics,
because IPI does not differentiate between the organism’s intrinsic pathogenicity and other factors (host and environment) that allow their expression. The
extreme alterations in host defence mechanisms in immunosuppressed patients
is a good example of the different pathogenicity of micro-organisms depending
on the specific type of systemic immunosuppression, i.e., neutropenia or cellular (T-lymphocyte) immune defect [17].
In general the classification of micro-organisms according to their pathogenicity is based on scales with few categories. Isenberg and D’ Amato [12] classify organisms as commonly involved, occasionally involved, and rarely
involved in disease production. Murray et al. [3] classify the pathogenicity of
organisms as high, potential, and low. Categories in both classifications are not
always equivalent.
We found that the classification of Murray et al. [3] (Table 4) is useful in
ICU practice because it is best adapted to flora isolated in ICU patients and is
more discriminatory between organisms of interest in the ICU. Another possible advantage is that this classification integrates other concepts of clinical epidemiology, such as “community” or “normal” and hospital or “abnormal” flora.
Antimicrobial Resistance as a Virulence Factor
The evaluation of the influence of antimicrobial resistance on mortality is difficult because of the requirement for adjustment for underlying disease and illness severity. Recent literature suggests that the factor of immediate, adequate
treatment plays an important role in the evaluation of the contribution of
antimicrobial resistance to mortality [18–21]. Fagon et al. [22] found that in
patients suspected of having ventilator-associated pneumonia an invasive strat-
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M.A. de la Cal, E. Cerdà, A. Abella, P. Garcia-Hierro
Table 4. Classification of micro-organisms based on their intrinsic pathogenicity [3]
(MRSA methicillin-resistant Staphylococcus aureus)
Intrinsic pathogenicity
Flora
Low pathogenic
Normal
Potentially pathogenic
Normal
Potentially pathogenic
Abnormal
Highly pathogenic
Abnormal
Indigenous flora
Oropharynx: peptostreptococci, Veillonella spp.,
Streptococcus viridans
Gut: Bacteroides spp., Clostridium spp.,
enterococci, Escherichia coli
Vagina: peptostreptococci, Bacteroides
spp., lactobacilli
Skin: Propionibacterium acnes,
coagulase-negative staphylococci
Community or normal micro-organisms
Oropharynx: Streptococcus pneumoniae,
Haemophilus influenzae,
Moraxella catarrhalis
Gut: Escherichia coli
Oropharynx and gut: Staphylococcus aureus,
Candida spp.
Hospital or abnormal micro-organisms
Klebsiella spp., Proteus spp., Enterobacter spp.,
Morganella spp., Citrobacter spp., Serratia spp.,
Pseudomonas spp., Acinetobacter spp., MRSA
Epidemic micro-organisms
Neisseria meningitidis, Salmonella spp.
egy based on the use of fiberoptic bronchoscopy improved the survival rate at
day 14 (p=0.02); 16.2% died in the invasive management group and 25.8% in the
clinical management group, i.e., a difference of 9.6%. This survival benefit can
be explained by the fact that significantly more patients who did not undergo
bronchoscopy received early, inadequate antimicrobial therapy (1 patient died
in the invasive group versus 24 in the control group, p<0.001). The survival benefit was only transient as the difference in mortality was not significant anymore at day 28 (p=0.10). Only a few of the evaluable studies have adjusted the
Classification of Micro-Organisms According to Their Pathogenicity
57
mortality data for appropriate antimicrobial treatment, underlying disease, and
illness severity.
Methicillin-Resistant S. aureus versus Methicillin-Sensitive S.
aureus
Of 31 bacteremia studies comparing mortality due to methicillin-resistant S.
aureus (MRSA) and methicillin-sensitive S. aureus MSSA [23], only 6 adjusted
for confounding factors including adequate antibiotic therapy [24–29]. Three
studies involving 401 patients did find a significantly increased mortality with
odds ratios varying between 3 and 5.6. The other 3 studies with a total of 1,385
patients did not show a significant difference. Only one study compared mortality due to MRSA in 86 bacteremic pneumonia patients without a significant
difference [30].
Vancomycin-Resistant Enterococci versus VancomycinSensitive Enterococci
Three studies in patients with positive blood cultures and adjusted for appropriate antibiotic treatment are available [31–33]. Only one study in 106 patients
reports a significantly higher mortality due to vancomycin-resistant enterococci (VRE) with an odds ratio of 4.0 (1.2–13.3). The other two studies in a total of
467 patients failed to show a mortality difference.
Aerobic Gram-Negative Bacilli Including Acinetobacter spp. and
Pseudomonas aeruginosa
One study in 135 patients compared mortality in patients with infections due to
piperacillin-resistant P. aeruginosa and mortality in patients with infections due
to sensitive P. aeruginosa [34]. Mortality data were not adjusted for immediate,
adequate antimicrobial therapy, as there was no difference in crude mortality.
There are no data on Acinetobacter mortality, whether sensitive or resistant.
These data show that the association of antimicrobial resistance to mortality has not yet been appropriately evaluated. The present evidence supports the
concept that antibiotic resistance does not contribute to mortality.
Conclusions
Although the properties of the different micro-organisms fail to explain completely their pathogenicity, it is clear that some characteristics determine the
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different pathogenicity, for example encapsulated pneumococci are more virulent than non-encapsulated pneumococci. Advances in molecular biology make
it possible to characterize some virulence factors that allow micro-organisms to
overcome the set of obstacles to accomplish infection. These include selection
of the niche and adherence to human body surfaces or medical devices (i.e.,
adhesins), competition with pre-existing organisms in some cases, impairment
of the host defence mechanism (i.e., antiphagocytic capsules, toxins), and production of tissue damage (i.e., toxins, enzymes). A recent paper discusses the
impact of critical illness on the expression of virulence in gut flora [35]. It has
been hypothesized that gut bacteria change and become more virulent as the
micro-organisms sense that the host’s capacity to control them is severely
impaired. Identification of the virulent genes also provides a better understanding of the relationship between virulence factors and their clinical expression [36] and can be helpful in epidemiological studies, such as in the determination of transmission, carriage, colonization, and infection routes with specific micro-organisms and the investigation of outbreaks [37].
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Isenberg HD (1988) Pathogenicity and virulence: another view. Clin Microbiol Rev
1:40–53
Brachman PS (1992) Epidemiology of nosocomial infections. In: Bennett JV,
Brachman PS (eds) Hospital infections, 3rd edn. Little Brown, Boston, pp 3–20
Murray AE, Mostafa SM, van Saene HKF (1991) Essentials in clinical microbiology. In:
Stoutenbeek CP, van Saene HKF (eds) Infection and the anaesthetist, vol 5. Bailliere
Tindall, London, pp 1–26
McCloskey RV (1979) Microbial virulence factors. In: Mandell GL, Douglas RG,
Bennett IE (eds) Principles and practice of infectious diseases, 1 st edn, vol 1. Wiley,
NewYork, pp 3–11
Pfaller MA, Herwald LA ( 1988) Laboratory, clinical, and epidemiological aspects of
coagulase-negative staphylococci. Clin Microbiol Rev 1:281–299
Freeman I, Platt R, Sidebottom DG et al (1987) Coagulase-negative staphylococcal
bacteremia in the changing neonatal intensive care unit population. JAMA
258:2548–2552
Kerver AIH, Rommes IH, Mevissen-Verhage EAE et al (1987) Colonization and infection in surgical intensive care patients. Intensive Care Med 13:347–351
Leonard EM, van Saene HKF, Shears P, Walker I, Tam PKH (1990) Pathogenesis of colonization and infection in a neonatal surgical unit. Crit Care Med 18:264–269
van Saene HKF, Stoutenbeek CP, Zandstra DF, Gilberston A, Murray A, Hart CA (1987)
Nosocomial infections in severely traumatized patient: magnitude of problem, pathogenesis, prevention and therapy. Acta Anaesthesiol Belg 38:347–356
van Saene HKF, Damjanovic V, Murray AE, de la Cal MA (1996) How to classify infections in intensive care units—the carrier state, a criterion whose time has come? J
Hosp Infect 33:1–12
Classification of Micro-Organisms According to Their Pathogenicity
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
59
Tramont EC (1979) General or nonspecific host defense mechanisms. In: Mandell GL,
Douglas RG, Bennett IE (eds) Principles and practice of infectious diseases, lst edn, vol
1. Wiley, NewYork, pp 13–21
Isenberg HD, D’ Amato RF ( 1990) Indigenous and pathogenic micro-organisms of
humans. In: Mandell GL, Douglas RG, Bennett IE (eds) Principles and practice of
infectious diseases, 3rd edn, vol 1. Churchill Livingstone, New York, pp 2–14
Jordan GW, Wong GA, Hoeprich PB (1976) Bacteriology of the lower respiratory tract
as determined by fiberoptic bronchoscopy and transtracheal aspiration. J Infect Dis
134:428–435
van der Waaij D (1992) Selective gastrointestinal decontamination: history of recognition and measurement of colonization of the digestive tract as an introduction to
selective gastrointestinal decontamination. Epidemiol Infect 109:315–326
Mackowiak PA, Martin RM, Smith LW (1979) The role of bacterial interference in the
increased prevalence of oropharyngeal Gram-negative bacilli among alcoholics and
diabetics. Am Rev Respir Dis 120:289–593
Leonard EM, van Saene HKF, Stoutenbeek CP, Walker I, Tam PKH (1990) An intrinsic
pathogenicity index for micro-organisms causing infection in a neonatal surgical unit.
Microb Ecol Health Dis 3:151–157
Shelhamer IH, Toews GB, Masur H et al (1992) Respiratory disease in the immunosuppressed patient. Ann Intern Med 117:415–443
Alvarez-Lerma F (1996) Modification of empiric antibiotic treatment in patients with
pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study
Group. Intensive Care Med 22:387–394
Luna CM, Vujacich P, Niederman MS et al (1997) Impact of BAL data on the therapy
and outcome of ventilator-associated pneumonia. Chest 111:676–685
Iregui M, Ward S, Sherman G, Fraser VJ, Kollef MH (2002) Clinical importance of
delays in the initiation of appropriate antibiotic treatment for ventilator associated
pneumonia. Chest 122:262–268
Valles J, Rello J, Ochagavia A, Garnacho J, Alcala MA (2003) Community-acquired
bloodstream infection in critically ill adult patients: impact of shock and inappropriate antibiotic therapy on survival. Chest 123:1615–1624
Fagon JY, Chastre J, Wolff M et al (2000) Invasive and noninvasive strategies for management of suspected ventilator associated pneumonia. A randomized trial. Ann Intern
Med 132:621–630
Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y
(2003) Comparison of mortality associated with methicillin-resistant and methicillinsusceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis
36:53–59
Conterno LO, Wey SB, Castelo A (1998) Risk factors for mortality in Staphylococcus
aureus bacteremia. Infect Control Hosp Epidemiol 19:32–37
Romero-Vivas J, Rubio, M Fernández C, Picazo JJ (1995) Mortality associated with
nosocomial bacteremia due to methicillin-resistant Staphylococcus aureus. Clin Infect
Dis 21:1417–1423
Harbarth S, Rutschmann O, Sudre P, Pittet D (1998) Impact of methicillin resistance on
the outcome of patients with bacteremia caused by Staphylococcus aureus. Arch Intern
Med 158:182–189
Soriano A, Martínez JA, Mensa J et al (2000) Pathogenic significance of methicillin
resistance for patients with Staphylococcus aureus bacteremia. Clin Infect Dis
30:368–373
60
M.A. de la Cal, E. Cerdà, A. Abella, P. Garcia-Hierro
28.
Mylotte JM, Tayara A (2000) Staphylococcus aureus bacteremia: predictors of 30-day
mortality in a large cohort. Clin Infect Dis 31:1170–1174
Topeli A, Unal S, Akalin HE (2000) Risk factors influencing clinical outcome in
Staphylococcus aureus bacteraemia in a Turkish University Hospital. Int J Antimicrob
Agents 141:57–63
González C, Rubio M, Romero-Vivas J, González M, Picazo JJ (1999) Bacteremic pneumonia due to Staphylococcus aureus: a comparison of disease caused by methicillinresistant and methicillin-susceptible organisms. Clin Infect Dis 29:1171–1177
Garbutt JM, Ventrapragada M, Littenberg B, Mundy LM (2000) Association between
resistance to vancomycin and death in cases of Enterococcus faecium bacteremia. Clin
Infect Dis 30:466–472
Vergis EN, Hayden MK, Chow JW et al (2001) Determinants of vancomycin resistance
and mortality rates in enterococcal bacteremia. A prospective multicenter study. Ann
Intern Med 135:484–492
Lodise TP, McKinnon PS, Tam VH, Rybak MJ (2002) Clinical outcomes for patients
with bacteremia caused by vancomycin-resistant enterococcus in a level 1 trauma center. Clin Infect Dis 34:922–929
Trouillet JL, Vuagnat A, Combes A, Kassis N, Chastre J, Gibert C (2002) Pseudomonas
aeruginosa ventilator-associated pneumonia: comparison of episodes due to piperacillin-resistant versus piperacillin-susceptible organisms. Clin Infect Dis 34:1047–1054
Alverdy JC, Laughlin RS, Wu L (2003) Influence of the critically ill state on host-pathogen interactions within the intestine: gut-derived sepsis redefined. Crit Care Med
31:598–607
Relman DA, Falkow S (1990) A molecular perspective of microbial pathogenicicty. In:
Mandell GL, Douglas RG, Bennett IE (eds) Principles and practice of infectious diseases, 3rd edn, vol 1. Churchill Livingstone, New York, pp 25–32
Emori TG, Gaynes RG (1993) An overview of nosocomial infections, including the role
of the microbiology laboratory. Clin Microbiol Rev 6:428–442
29.
30.
31.
32.
33.
34.
35.
36.
37.