healthmedicinet

With the experience gained in the two previous projects, a new project named “Zero
Resistance” was developed by the SEMICYUC with the support of the Spanish Ministry
of Health. This project uses the same structure created for “Zero Bacteremia” and
“Zero VAP”, which is based on coordination at national, regional and local levels.

A Scientific Expert Committee (SEC) for the development and implementation of this
program was appointed as follows: SEMICYUC nominated nine intensivists chosen for
their expertise in the field of prevention and management of infections in the critical
care setting and SEEIUC designated an intensive care nurse with experience in infection
control. A microbiologist, an epidemiologist, an infectious diseases specialist, and
two technicians from the Ministry of Health with broad knowledge in the field were
also incorporated.

The members of the SEC reviewed the available evidence in PubMed indexed papers, including
observational studies, clinical trials, guidelines, systematic reviews and meta-analyses.
The following databases were searched: Medline, Embase, the Cochrane Library, and
Centre for Reviews and Dissemination, including the National Health Service Economic
Evaluation Database and the Health Technology Assessment database.

The implementation of ‘bundles’ of effective measures, compared to individual interventions,
has been proposed to reduce the incidence of catheter-related bloodstream infections
or VAP 14],15]. With this concept in mind, the SEC developed a bundle of 10 recommendations that
was discussed and approved after review and analysis of the existing scientific literature.
Admittedly, the evidence supporting some of the chosen recommendations is weak, but
all were deemed to reach at least the level of ‘expert recommendation’. No grading
system was used to support the strength and quality of recommendations. All items
include comments intended to facilitate local adaptations.

Criteria for defining MDR pathogens vary from institution to institution and are also
not uniform in the published literature, although the most highly resistant strains
are readily recognizable. Based on the pathogens considered most problematic in Spanish
ICUs, “Zero Resistance” collects information on episodes of infection and colonization
of the pathogens listed in Table 1. Finally, because acquiring an infection may be the result of errors in patient-care,
all three programs were designed to reduce and prevent these by incorporating an integral
patient safety program 16].

Table 1. Definitions of multidrug-resistant bacteria monitored in theZero Resistanceprogram

Objectives

The main objective of the “Zero Resistance” project is reduction in the cumulative
incidence of patients with ICU-acquired MDR infections by 20%. Secondary objectives
are to study the epidemiology of MDR infections in Spanish ICUs, to be able to distinguish
imported from ICU-acquired cases, to promote and strengthen safety assurance in participating
units, and to create a network of ICUs implementing safe, and evidence-based practices.
“Zero Resistance” has been active since April 2014.

The bundle

The primary aim of the bundle recommendations is reduction of the three most influential
factors contributing to the development and transmission of MDR, namely: 1) adequate
prescription of antibiotics; 2) early detection and prevention of cross-colonization
of MDR; and 3) elimination of reservoirs 8].

1.
First recommendation: In each ICU, at least one intensivist will be designated as
responsible for the use of antimicrobials. He/She should have extensive experience
in infection control and in the treatment of severe infections. This/these physician(s)
should routinely assess antimicrobial prescription and advise attending clinicians.
Analysis of antimicrobial use should include:

a.
Review of the indication for antimicrobials,

b.
Evaluation of the appropriateness of the antimicrobial and the correct administration
(dosing, intervals and duration),

c.
Evaluation of de-escalation of antimicrobial therapy or even antimicrobial cessation.

Rationale: Antibiotic prescription in the critical care setting is a complex task
that requires profound and extensive knowledge. Moreover, many pathophysiological
changes associated with severe acute illness or sepsis, like capillary leak, third
spacing, increased volume of distribution, and impaired renal and/or liver function,
affect antimicrobial pharmacokinetics/pharmacodynamics 17]. Therefore, it is imperative to identify intensivists with a profound knowledge of
infectious diseases in critically ill patients in order to improve prescription quality.
This implies choosing optimal empirical antibiotics, appropriate mode of administration,
and correct dosage. Administration of antimicrobials to severely ill patients at dosages
defined in studies conducted in healthy volunteers often achieves only suboptimal
serum concentrations, which are associated with treatment failure and resistance development
17],18].

Prompt and adequate antimicrobial therapy reduces morbidity and mortality in severe
sepsis and septic shock 19]. However, as soon as microbiological information is available, empiric therapy should
be adapted, if appropriate, by either reduction in number and/or narrowing of antimicrobial
spectrum. Notwithstanding, many clinicians are reluctant to stop antimicrobials if
the patient is improving. In fact, de-escalation of empirical therapy is performed
in less than 50% of patients 20]. Recent studies have shown that de-escalation is safe even in critically ill patients
with severe sepsis 21] or immunosuppression 22].

2.
Second recommendation: Empirically administer antimicrobials active against MDR pathogens
only in cases of severe sepsis or septic shock and high risk of MDR pathogen(s) based
on patient risk factors and/or knowledge of local ecology. Otherwise, narrow-spectrum
or withholding of antimicrobials is recommended until microbiological results become
available and targeted therapy with antibiotics active against MDR pathogens (carbapenems,
colistin, tigecycline, glycopeptides, daptomycin, linezolid) should be started if
needed. In all cases, samples for culture of the potential sources of infection should
be obtained before starting antibiotic therapy.

Rationale: Early and adequate antimicrobial therapy is associated with increased survival
in patients with severe sepsis and septic shock 19]. However, delaying antimicrobial therapy until microbiological confirmation is available
has been shown to be associated with similar outcomes in febrile surgical ICU patients
compared to starting antimicrobials immediately after the clinical diagnosis of infection
23]. More recently, a quasi-experimental, before-after observational cohort study concluded
that, after adjusting for confounders, aggressive antimicrobial therapy was an independent
predictor of mortality. In the aggressive period, antimicrobial treatment was always
started in patients suspected of having an infection after appropriate cultures were
obtained. In the second period (conservative strategy), antimicrobial treatment was
started only after objective findings confirmed the infection 24].

The main limitation of both studies is that they were carried out in surgical patients
and data from medical units are lacking. However, it is important to keep in mind
that in febrile patients with severe sepsis or septic shock a delay in antimicrobial
therapy may be fatal. In addition, the choice of empirical antimicrobial therapy should
be based on an updated knowledge of the local ecology. Therefore, it seems prudent
to recommend starting empiric antimicrobials active against MDR pathogens immediately
only in cases meeting criteria for severe sepsis or septic shock and risk factors
for MDR pathogens. Obviously, efforts to reduce the delay of microbiological results
(use of rapid diagnostic techniques, direct contact with the microbiologist …) and
close follow-up of the clinical course to rapidly detect signs of alarm are fully
endorsed.

3.
Third recommendation: In each Unit, at least one nurse will be designated as leader
of this project and responsible for infection control measures aimed at reducing transmission
of MDR pathogens.

Rationale: Success of quality control programs is particularly dependent on the involvement
of all categories of healthcare professionals. Nurses play a critical role in preventing
and controlling infectious diseases and measures to prevent patient-to-patient transmission
are a significant component of care.

A multidisciplinary team approach is necessary to develop and implement strategies
to prevent infection in the critically ill patient. The participation of nurses is
of extraordinary importance for the success of infection control programs in intensive
care 25],26]. In fact, most procedures performed to reduce the risk of nosocomial infection (vascular
catheter care, artificial airway care, mouth hygiene, etc.) are part of the nurse’s
daily tasks.

Programs that have achieved significant reductions in nosocomial infection rates have
designated at least one physician and one nurse in each ICU as team leaders 14]. This model has also been implemented by successful programs designed to reduce nosocomial
infection rates in the ICU endorsed by SEMICYUC 11]. The “Zero Resistance” program clearly supports the nomination in every ICU of a
nurse leader responsible for infection control to reduce nosocomial infections and
transmission of MDR pathogens.

4.
Fourth recommendation: It is recommended to perform an active search for MDR pathogens
in all patients on admission to the unit and at least once a week throughout their
stay. These samples will be processed to identify MDR pathogens according to the local
epidemiology and in collaboration with the Microbiology Service and Infection Control
Team of each hospital.

Rationale: Guidelines for MDR organisms include recommendations for routine screening
cultures and contact precautions for patients after admission to high-risk units,
e. g., ICUs 6],27]. The implementation of contact precautions in patients colonized or infected with
MDR is widely accepted. In contrast, the use of routine surveillance cultures in MDR
management is still a matter of debate and not widely performed 28]. Initial screening is specially recommended for MRSA, although the same principles
and practices apply to Gram-negative MDR organisms, which actually now constitute
the main threat.

Active surveillance programs are time and resource-consuming. The type and number
of samples are selected according to local resources and epidemiology and should include
at least nasal, rectal and oropharyngeal swabs (bronchial aspirates in intubated patients)
29]. In addition, other samples may be necessary to control potential reservoirs (infections,
skin ulcers, etc.).

Concerning surveillance cultures, two approaches are acceptable: All patients are
screened at ICU admission or only those patients with at least one of the risk factors
included in the checklist (see Fifth Recommendation).

5.
Fifth recommendation: At admission to the ICU, a ‘Checklist’ of risk factors (Table 2) must be completed to identify patients at high risk of MDR pathogen carriage. Patients
meeting at least one of the risk factors must be cared for under application of contact
precautions pending culture results.

Table 2. Checklist of risk factors for carriage of multidrug-resistant (MDR) bacteria

Rationale: Several risk factors associated with carriage of MDR at admission to the
hospital or to the ICU have been identified: Prior antibiotic use, the presence of
invasive devices and certain underlying diseases are the most frequently reported
30]. Patients at risk of nosocomial pneumonia caused by MDR pathogens according to American
Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria are: Current
hospitalization of 5 days or more, prior antibiotic therapy, prior hospitalization,
residence in a nursing home or extended-care facility, home infusion therapy within
30 days, chronic dialysis within 30 days, home wound care, family member with an MDR
pathogen, and immunosuppression. However, in a prospective evaluation, although these
criteria had an excellent negative predictive value (96%), they had a very low positive
predictive value (18%) for infection or colonization with an MDR pathogen at ICU admission
31]. In a case–control study, immunosuppression was not independently associated with
MDR bacteria in the ICU 32].

In other studies, risk factors for specific pathogens, like MRSA or A. baumannii, have been identified in an attempt to establish control measures that limit spread
33]. This approach is particularly indicated in ICUs in which a particular microorganism
causes the majority of episodes of colonization/infection.

With this information, the SEC generated a Checklist (Table 2) for detection of patients at high risk of carrying MDR pathogens. If one or more
of these risk factors is present, screening cultures at ICU admission is mandatory
and the patient must be placed in contact isolation until culture results are negative
for the target organisms. The prospective validation of this Checklist is one of the
pending tasks of this program.

6.
Sixth recommendation: Compliance with preventive measures including those based on
transmission mechanisms should be routinely measured.

Rationale: Contact precaution and hand hygiene are the mainstay for reducing transmission
of microorganisms 34],35]. Adherence to these practices must be continuously reinforced and monitored 36]. Briefly, contact precautions (by staff and visitors) consist of: Hand hygiene and
donning of gown and gloves immediately prior to room entry, and disposal of gown and
gloves inside the patient’s room, followed by hand hygiene immediately prior to leaving
the room.

Adherence rates for contact precautions in ICU settings with availability of all facilities
were between 75 and 80% in one study 8]. Correct practice includes: (1) Use of a contact precautions sign for every patient
colonized/infected by MDR pathogens; (2) availability of contact precautions equipment
at patient room entry; (3) barrier disposal containers inside patient room; and (4)
monitoring of adherence to the contact precautions protocol by staff/visitors. If
there are no closed rooms, precautions must be tightened.

To achieve the desired results, all staff members should watch compliance with preventive
measures. Concerning this issue, the SEC of “Zero Resistance” considers that nurses
have a special responsibility in implementing effective prevention. Therefore, the
rest of the hospital staff and visitors must follow their recommendations.

7.
Seventh recommendation: All Units should develop a cleaning protocol for rooms of
patients with MDR pathogens.

Rationale: Many published outbreaks of MDR pathogens detect a common source on environmental
surfaces and in moist areas. Studies have documented a widespread deficiency in cleaning
practices. Nevertheless, substantial improvements in cleaning and disinfection can
be achieved by using standardized protocols in the ICU 37]-39]. Cleaning procedures must be adapted to the architectural characteristics of each
unit and agreed upon with the cleaning staff and the nosocomial infection control
committee. Feedback to all involved personnel is imperative to maintain the benefits.
This protocol should include fixed structures (floors and walls) as well as the bed
(including main structure, rails and mattress). Cleaning protocols will include daily
cleaning and final cleaning at patient discharge. Cleaning protocols for rooms occupied
by patients with MDR pathogens must specify methodology, frequency of cleaning and
disinfectant products. Because different cleaning products are approved in each hospital,
the exact composition or trademark should be specified in the protocol. If deemed
necessary, controls will be established to ensure MDR eradication 39].

8.
Eighth recommendation: A file/document specifying the existing equipment in the ICU
and its respective cleaning protocols should be available and updated.

Rationale: Any clinical or technological equipment could act as a microbiological
reservoir for MDR pathogens. Therefore, the first action is to remove all expendable
materials, leaving work surfaces as free as possible. Equipment should be filed and
information on the following aspects provided: Staff responsible for cleaning, cleaning
schedule and cleaning methodology (disinfection, sterilization). Each healthcare worker
is responsible for cleaning and disinfection of equipment for personal use (stethoscopes,
flashlights …) 40].

9.
Ninth recommendation: To include products containing 4% chlorhexidine in daily patient
hygiene if colonized or infected with MDR pathogens.

Rationale: Several observational studies and single-center trials have concluded that
daily chlorhexidine bathing of ICU patients reduces the acquisition of MDR pathogens
and the incidence of certain infections 40]-43]. A systematic review concluded that chlorhexidine body-washing may be effective in
preventing carriage, and possibly bloodstream infections, with Gram-positive MDR pathogens
(MRSA and vancomycin-resistant enterococci [VRE]), whereas the evidence that this
intervention eradicates carriage or prevents infection with Gram-negative MDR pathogens
is weak 44].

In a recent randomized multicenter trial carried out in 13 ICUs, the effect of different
infection control strategies on acquisition of MDR pathogens was assessed. Improved
hand hygiene plus unit-wide chlorhexidine body-washing reduced acquisition, particularly
of MRSA 45]. Interestingly, in the context of sustained high level compliance of hand hygiene
and chlorhexidine bathing, screening and isolation of carriers did not reduce acquisition
rates of MDR pathogens. More recently, a multicenter, open, crossover trial documented
the clinical benefits of daily bathing with chlorhexidine-impregnated washcloths in
reducing the risks of acquisition of MDR and the development of hospital-acquired
bacteremia 46].

Chlorhexidine solutions must contain 0.16 grams of chlorhexidine (digluconate) per
liter (dissolve 20 ml of 4% chlorhexidine in 1 liter of warm water). Contraindications
for chlorhexidine use and adverse reactions should be taken into account. Because
chlorhexidine is a cationic molecule, its activity can be reduced by natural soaps,
various inorganic anions, non-ionic surfactants, and hand creams containing anionic
emulsifying agents. Daily chlorhexidine bathing is simple to implement and relatively
inexpensive and may be an important adjunctive intervention to barrier precautions
to reduce acquisition and the subsequent development of infection.

10.
Tenth recommendation: If an outbreak is suspected it is recommended to identify the
causative organism with molecular typing methods.

Rationale: Studies of outbreaks based on the phenotypic characteristics of microorganisms
(antigenic properties, metabolic or antibiotic resistance) are limited and do not
provide conclusive differences or similarities between them. Therefore, molecular
typing methods, to be able to recognize epidemiologically-linked isolates derived
from a common precursor microorganism, should be performed. This will also provide
understanding of the mechanism of transmission and dissemination and allow strategies
to control and eradicate the epidemic to be designed 47],48].

The “Zero Resistance” program encourages hospitals without resources for molecular
testing to send MDR isolates to a Reference Laboratory (National Center for Microbiology,
Institute of Health Carlos III; 49]), where the microbiological test will be performed free of charge.