Antibiotic Policies in the Intensive Care UnitH.K.F.

Antibiotic Policies in the Intensive Care Unit

H.K.F.

S

, N.J. R

, A.

S

, G. N

Why Does an Intensivist Need an Antibiotic Policy?

Every intensive care unit (ICU) should have well-structured guidelines on the use of antimicrobial agents to guarantee that patients requiring intensive care receive appropriate antimicrobials for a relevant period to prevent and treat infections.

These guidelines should meet the therapeutic needs of the consultants and allow the intensivist, clinical microbiologist, and pharmacist to monitor efficacy, toxici- ty, including allergy and diarrhea, and side-effects, such as the emergence of resist- ant strains and subsequent outbreaks of superinfections. Calculation of infection rates is only feasible following the implementation of an antibiotic policy. Apart from audit and research, antimicrobial guidelines aid educational programs and enable the clinical pharmacist to control drug expenditure.

Main Feature of Antibiotic Guidelines

The main feature of an antibiotic policy in the ICU is the use of a minimum of well-established antimicrobial agents that are associated with a minimum of side- effects, but also allow the control of the three patterns of ICU infections due to the 15 potentially pathogenic micro-organisms (PPM) (Chapters 4 and 5).

Antimicrobials Chosen on the Basis of Three Characteristics

Preservation of Indigenous Flora

Control of the abnormal flora, including (potentially resistant) aerobic gram-

negative bacilli (AGNB) and methicillin-resistant Staphylococcus aureus

(MRSA), by normal indigenous mainly anaerobic flora is termed “microbial ecology” [1]. The normal flora has been shown to provide resistance to acquisi- tion and subsequent carriage of PPM, and constitutes the microbial component of the carriage defense (Chapter 2). Antimicrobial agents that are active against the indigenous anaerobic flora, and that are excreted into throat and gut via saliva, bile, and mucus in lethal concentrations, may suppress the indigenous flora. Diarrhea and candidiasis are well known side-effects of commonly used antibiotics. The use of antimicrobial agents that disregard ecology leads to an impaired microbial factor of the carriage defense and promotes overgrowth of abnormal AGNB [2] and MRSA [3], as well as Clostridium difficile [4] and van- comycin-resistant enterococci (VRE) [5]. Narrow-spectrum antimicrobials can be defined as antimicrobials that only cover the 15 aerobic PPM, leaving the indigenous normal flora more or less intact [6]. Broad-spectrum antimicrobials are not only active against the 15 disease-causing PPM but also affect the nor- mal indigenous anaerobic flora that contributes to physiology rather than infection. From an ecological perspective, ampicillin, amoxycillin, and flu- cloxacillin are antimicrobials with a spectrum that is broader than that of cephradine and cefotaxime [7–11]. The most recent ever more potent antimi- crobials generally belong to the group of ecology disregarding antimicrobials that predispose to, e.g., AGNB, MRSA, and yeast overgrowth and subsequent superinfection [3, 12–15] (Table 1).

Table 1. Classification of parenteral antimicrobials based on respect for ecology

Indigenous flora friendly Indigenous flora suppressing

Challenge studies in volunteers

cephradine ampicillin

cefotaxime amoxicillin

Comparative studies in patients

cephradine amoxicillin

penicillin ampicillin

Observational studies in patients

gentamicin flucloxacillin

tobramycin amoxicillin + clavulanic acid

amikacin piperacillin + tazobactam

polymyxins ciprofloxacin

polyenes carbapenems

metronidazole macrolides

Limitation of the Emergence of Resistant Microbes by Using Antimicrobials with the Lowest Resistance Potential

If resistance occurs during drug development or clinical trials, or within 2 years of general use, the antibiotic has a high resistance potential [16].

Ceftazidime-resistant, ciprofloxacin-resistant, and imipenem-resistant Pseudomonas aeruginosa were reported during clinical trials and early after were introduced for general use [17–19]. Antimicrobials with little or no resist- ance potential include cephradine, piperacillin, cefotaxime, amikacin, and meropenem (Table 2) [19–22]. Three observations have emerged from this his- torical experience: (1) each antibiotic class has one or more antimicrobials capable of causing antibiotic resistance, but this is not a class phenomenon;

antibiotic resistance is agent specific; (2) resistance is not related to duration of use; and (3) resistance is not related to volume of use.

Table 2. Classification of parenteral antimicrobials based on the potential for resistance

Low resistance High resistance

piperacillin ampicillin

cephradine ceftazidime

cefotaxime gentamicin

cefepime ciprofloxacin

amikacin imipenem

levofloxacin meropenem

The underlying mechanisms explaining the difference between antibiotics

with a high and a low resistance potential are not fully understood, but are

thought to be based on specific antibiotic resistance mechanisms. For example,

among the aminoglycosides, only gentamicin has been associated with wide-

spread P. aeruginosa resistance, but amikacin continues to be effective against

most gentamicin-resistant P. aeruginosa. Gentamicin is an aminoglycoside that

is highly susceptible to inactivation by a variety of enzymes at six different loci

on the gentamicin molecule, but amikacin has only one such vulnerable point

that is subject to enzyme inactivation [23]. It was postulated that the substitu-

tion of amikacin for gentamicin would decrease P. aeruginosa susceptibilities

to gentamicin. The substitution of amikacin for gentamicin decreased gentam-

icin-resistant P. aeruginosa when amikacin was used in the same volume as gen- tamicin, and no subsequent resistance problems developed. Some institutions with renewed gentamicin susceptibility to P. aeruginosa returned to using gen- tamicin as the major hospital aminoglycoside (i.e., rotating formularies) [24].

Predictably, gentamicin-resistant P. aeruginosa isolates returned to previous levels and were perpetuated as long as gentamicin was the primary aminogly- coside used in the hospital and ICU. Some people believe that these aminogly- coside lessons of the past should be applied to the problems of P. aeruginosa resistant to ceftazidime, ciprofloxacin, and imipenem. The substitution of cefepime, levofloxacin, and meropenem for ceftazidime, ciprofloxacin, and imipenem may decrease or even eliminate resistant P. aeruginosa from the ICU environment [25–27]. According to the concept of low and high resistance potential of antimicrobial agents, the key to controlling antibiotic resistance is agent related, and is not class, duration, or volume associated.

Control of Inflammation by Using Antimicrobials with Anti- endotoxin/Inflammation Properties

Lipopolysaccharide (LPS) or endotoxin is the major component of the outer membrane of AGNB, and is thought to be a key molecule in the induction of generalized inflammation. LPS causes the production and release from host effector cells of various pro-inflammatory cytokines and other mediators of inflammation, such as nitric oxide and prostaglandins. The degree to which these mediators are released depends, in part, on the amount of LPS that is pre- sented to CD14-bearing effector cells such as monocytes, macrophages, and polymorphonuclear leukocytes. Therefore, it is possible that factors that affect the amount of LPS that is released in vivo may modulate the inflammatory response associated with AGNB infection. Several in vitro and animal studies show that antimicrobial agents may differentially release LPS from AGNB [28, 29]. They also demonstrated that antibiotics associated with substantial release of endotoxin result in the generation of higher levels of pro-inflammatory cytokines, and suggested that the use of antimicrobials associated with the release of lower amounts of LPS leads to lower levels of cytokinemia and better outcome. Carbapenems such as imipenem and meropenem have been shown to release a small amount of endotoxin, whilst third-generation cephalosporins such as ceftazidime and cefotaxime are associated with far greater release of endotoxin [30]. Three clinical trials failed to support this hypothesis that dif- ferential antibiotic-induced endotoxin release is of clinical significance, as there were no significant differences in clinical parameters (temperature, blood pres- sure, or heart rate) or plasma endotoxin and cytokine levels [31–33].

Fluoroquinolones such as ciprofloxacin release substantial amounts of

endotoxin compared with the aminoglycosides gentamicin and tobramycin and

with the polymyxins both E (colistin) and B [34, 35]. Although not active against AGNB, glycopeptides, including teicoplanin [36] and vancomycin [37], and polyenes, such as amphotericin B [38], have been shown to downregulate the LPS-induced cytokine release (Table 3).

Table 3. Classification of antimicrobials based on their anti-inflammation propensities

Inflammation controlling Inflammation promoting

aminoglycosides β-lactams

glycopeptides cefotaxime

ceftazidime

polymyxins

fluoroquinolones polyenes

ciprofloxacin carbapenems

The classification of antimicrobials using these three criteria of flora friendliness, low resistance potential, and anti-inflammation propensity is not evidence based, i.e., not evaluated in randomized trials. However, despite the lack of level 1 evidence, we found the available data compelling and difficult to ignore in selecting antimicrobials for our antibiotic policy.

The use of a limited number of antimicrobial agents allows the control of the 15 potential pathogens implicated in the three types of ICU infections. The main groups are: (1) the β-lactams, i.e., antibiotics with a β-lactam ring in their structure such as penicillins and cephalosporins, (2) the aminoglycosides, e.g., tobramycin, (3) the polymyxins, e.g., polymyxin E or colistin, (4) the glycopep- tides, e.g., vancomycin, and (5) polyenes such as amphotericin B.

All these antimicrobial agents are lethal to micro-organisms. The polymyx-

ins, glycopeptides, and polyenes have a rapid action on the microbial cell mem-

brane. The β-lactams interfere with the cell wall synthesis, a slower mechanism

of action. The aminoglycosides inhibit the synthesis of protein, but still kill

microbes in the rest phase. These differences in mechanism of action may

explain why aminoglycosides and polyenes are more toxic to the ICU patient

than β-lactams when parenterally administered. Table 4 shows the spectrum of

activity of the five main antimicrobial groups according to the minimal bacte-

ricidal concentration (MBC) for the 15 PPMs. The MBC of an antimicrobial

agent is defined as the amount of the antimicrobial (mg/l) required to establish

irreversible inhibition in the test tube, without the support of the killing activ-

ity of the leukocytes of the ICU patient. Leukocytes of the critically ill are

thought to be less effective in killing PPM than those of a healthy population [39]. Antimicrobial agents with an MBC of ≤1 mg/l for PPM are in general suit- able for clinical use. Non-toxic antibiotics such as the β-lactams are ideal for systemic administration, and high doses (50-100 mg/kg per day) can be given.

The more toxic agents, such as the polymyxins and the polyenes, can be safely applied enterally and topically in high doses. Polyenes given parenterally are toxic and the daily doses are in the order of milligrams (1.5 mg/kg per day for amphotericin B). Aminoglycosides and glycopeptides, although toxic, are administered systemically in lower doses (5–25 mg/kg per day).

Antimicrobial Use for Both Prophylaxis and Therapy Falls into Three Categories

Parenteral Antimicrobials

Parenteral antimicrobials aim to prevent and, if already present, to eradicate colonization/infection of the internal organs, including blood, lungs, and blad- der. Systemic prophylaxis is generally accepted in surgery [40]. The aim is to achieve a tissue concentration at the time of the surgical trauma in order to pre- vent wound infections. Patients who require intensive care due to an acute trau- ma or worsening of the underlying disease invariably receive invasive devices, including ventilation tube, urinary catheter, and intravascular lines. These interventions are well known risk factors for lower airway, bladder, and blood- stream infections in the ICU patient whose immunoparalysis is at its nadir dur- ing the 1st week of admission. This is the time period during which primary endogenous infections occur. Only the immediate administration of parenteral antimicrobials enables the prevention of this type of infection and the early therapy of an already incubating primary endogenous infection. If the primary endogenous infection is the indication for admission to the ICU, parenteral antimicrobials are required to treat the established infection. The philosophy that prevention of infection is always better than cure dictates the immediate administration of systemic antibiotics to a critically ill patient requiring mechanical ventilation. Hence, systemic cefotaxime is an integral part of the concept of the prophylactic protocol of selective decontamination of the diges- tive tract (SDD) [41].

The criteria for parenteral antibiotics include flora friendliness and low

resistance potential (after excretion into throat and gut via saliva, bile, and

mucus) and anti-inflammation propensity. In addition, the pharmacokinetic

properties should include a high excretion in the target organs and in particu-

lar in the bronchial secretions. The ratio of the antimicrobial level in the target

organ and the MBC (Table 4) determine the efficacy against a particular micro-

Table 4.

Sp ec tr um o f ac ti v it y o f the c o mmo nl y used an ti micr o b ial agen ts f o r the 15 po ten tial p athogen s exp re ssed b y the minimal b ac ter icid al c o n- ce n tra tio n (MBC) (mg/l)

P enicil lin G C ep hradine C ef o taxime C ef tazidime Aminog ly cosides P o ly m yxin s Gl yc ope pt ides P ol yenes e.g .t o b ram ycin e.g . e.g . e.g . pol y m yxin E vanc o m ycin am pho ter icin B “N o rmal”

0.1 0. 2 (2)

0.06 0.2

11 1

0.02 0.2 0.2 0.1

1 1 (8.0) 0.2 0.05

p 0.05 “A b n o rmal”

0.1 0.1 0.1 0.1

0.1 0.1 0.2

0.1 0.1 0.2

0.3 0.3 0.1 0.1

0.2 0.2 0.1 0.1

11 0. 2

(8) (8) 0.1 0.1

- 0.1 0.1 0.5 MRSA 1.0

,p o ten tial ly p athogenic micr o-o rganism s;

,methicil lin-r esistan t

organism (Chapter 7). Protein binding should be minimal. The parenteral antimicrobial requires a good safety profile in terms of allergy, nephro- and ototoxicity, and influence on hemostasis. Finally, the target PPM is a criterion of paramount importance for the choice of a parenteral antimicrobial. Primary endogenous infections are caused by both “normal”, e.g., Streptococcus pneu- moniae, Haemophilus influenzae, and S. aureus, and “abnormal” potential pathogens, including AGNB and MRSA. General health before admission to the ICU influences the carrier state (Chapter 2). Previously healthy individuals such as trauma, burn, acute liver, and pancreatitis patients only carry normal poten- tial pathogens, whilst patients with chronic underlying diseases, including chronic obstructive pulmonary disease, diabetes, and alcoholism, may carry AGNB and MRSA. It is obvious that patients referred to the ICU from other hos- pitals or wards are highly likely to be carriers of abnormal potential pathogens.

Taking these criteria into consideration there are only a few antimicrobials suit- able for prophylaxis. The first- and second-generation β-lactams cover the nor- mal potential pathogens, but are less effective against the abnormal AGNB.

Cefotaxime, a third-generation cephalosporin, has an adequate spectrum towards both normal and abnormal AGNB, with the exception of P. aeruginosa and Acinetobacter species. Ceftazidime adequately covers AGNB, but at the expense of S. aureus. Cefepime may be a suitable alternative for ceftazidime.

Three randomized SDD trials used the fluoroquinolones ciprofloxacin and ofloxacin as systemic prophylaxis despite the inadequate cover of S. pneumoni- ae [42–44]. Most SDD studies employed cefotaxime as parenteral antimicrobial.

Many patients admitted to a medical/surgical ICU receive peri-operative pro- phylaxis. This surgical prophylaxis may be replaced by cefotaxime as soon as SDD is started. In patients in whom prosthetic material has been implanted, an appropriate endocarditis prophylaxis should also be given. It is not uncommon that patients with a generalized inflammation state on admission to the ICU receive an aminoglycoside to control inflammation, in addition to cefotaxime.

Colonization of the lower airways, in particular with S. aureus, MRSA, P.

aeruginosa, and Aspergillus fumigatus, may persist despite adequate systemic

therapy. Cephradine, vancomycin, polymyxin E, cefotaxime, ceftazidime, gen-

tamicin, tobramycin, and amphotericin B can be nebulized to achieve higher

antibiotic concentrations in the lower airways. The ventilation tube is often

contaminated and has to be changed and replaced by a new tube following neb-

ulization. Surveillance swabs of the oropharynx are required to monitor the

efficacy of the therapy. Chapter 23 discusses in detail the fundamental features

of infection therapy: (1) sterilization of the infected internal organ using par-

enteral antibiotic(s); (2) source elimination with enteral antibiotics; (3) removal

or change of the foreign device; and (4) evaluation of efficacy of therapy using

surveillance samples.

Enteral Non-Absorbable Antimicrobials

Enteral non-absorbable antimicrobials aim to prevent and, if already present, to eradicate carriage and overgrowth of abnormal flora from throat and gut. The abnormal carrier state always precedes secondary endogenous infections.

Whilst parenteral antimicrobials are required to control primary endogenous infections, enteral non-absorbable antibiotics aim to prevent secondary endogenous infections [45]. The commonly used decontaminating agents include polymyxin E, tobramycin, amphotericine B, or nystatin and van- comycin. They all fulfil the three requirements of narrow spectrum or ecology friendliness, low resistance potential, and anti-inflammation properties.

Additionally, they are non-absorbable in order to achieve high salivary and fecal concentrations, and as all antimicrobials they are inactivated by fiber, cells, and fecal material to varying extents. Tobramycin and polymyxin are min- imally and moderately inactivated, respectively. The polyenes and vancomycin require high oral doses due to a high inactivation rate (Chapter 9). For decont- aminating agents to be effective, a minimal contact time between antimicrobial and abnormal potential pathogen of 15 min is required. This contact time is no problem in the stomach and gut due to ileus, and is guaranteed by the applica- tion of a paste or a gel in the oropharynx. High failure rates of oral sprays and rinses of antimicrobials have been reported (Chapter 27). Apart from nystatin, all antimicrobials used for SDD are administered parenterally in spite of their toxicity. Toxicity is a lesser problem following enteral administration, even in high doses. Chapter 9 discusses the significant reductions in carriage of AGNB, yeasts, and MRSA following the enteral use of polymyxin/tobramycin, polyenes, and vancomycin. Interestingly, amongst the 15 target PPMs, three micro-organ- isms P. aeruginosa, Candida species, and MRSA are less easy to completely clear from the throat and/or gut. It is not uncommon that the surveillance swabs yield very low concentrations of yeasts, MRSA, and P. aeruginosa even during long-term SDD use. Apparently, reducing overgrowth to very low growth densi- ties is sufficient to control infection, resistance, and transmission [46, 47].

Topical Antimicrobials

Topical antimicrobials aim to prevent and, if already present, to eradicate colo-

nization/infection of abnormal flora from wounds in which plastic devices may

be present such as tracheostoma and gastrostoma. Wounds, in particular burn

wounds, are prone to acquisition and subsequent exogenous colonization/infec-

tion with potential pathogens such as P. aeruginosa and MRSA, without previ-

ous carriage in the digestive tract. Gels including aquaform and intrasite are

very suitable for the application of antimicrobials to burn wounds [48]. The

concentration of for example polymyxin E or vancomycin is in general 2%. Each

application has to be preceded by debridement of the wound and cleaning with a disinfecting agent such as 2% tauroline, to remove necrotic tissue that may inactivate polymyxin E or vancomycin. The transparent gels allow careful inspection of wound healing and granulating tissue. Tracheostoma and gas- trostoma are artificially created long-term wounds kept open by plastic devices.

Potential pathogens such as P. aeruginosa and non-aeruginosa, Acinetobacter baumannii, and S. aureus, both methicillin sensitive and resistant, have an intrinsic affinity for plastic. Colonization/infection of exogenous origin is not uncommon in patients with tracheostoma and/or gastrostoma. As it is virtual- ly impossible to sterilize plastic using parenteral agents, the devices have to be removed and the wounds to be cleaned with taurolin. A thin layer of a paste containing 2% of polymyxin E and/or vancomycin is applied to the stoma before a new device is put in. Obviously prevention of colonization/infection of tracheostoma and gastrostoma using the paste twice daily throughout ICU treatment is preferred to therapy of colonization/infection [49].

Efficacy in Relation to Duration of Antimicrobial Therapy

Parenteral Antimicrobials

The prevention of primary endogenous infection is the main reason for the use of parenteral antimicrobials, being one of the crucial components of the SDD protocol. Supplementary prophylaxis is the second reason for its use [50]: cover during establishment of SDD on mucosal surfaces, cover for procedurally released micro-organisms, and elimination from mucosal surfaces of PPM resistant to the enteral antimicrobials, e.g., S. pneumoniae is resistant to polymyxins, aminoglycosides, and polyenes.

The duration of parenteral prophylaxis as an integral part of SDD depends on the type of carrier state, i.e., normal versus abnormal. The maximum period of parenteral prophylaxis is 5 days for patients with abnormal flora. The oropharynx and gut (not rectal cavity) are expected to be free from abnormal AGNB and MRSA within 3 days of enteral antimicrobials. In patients who were previously healthy, a shorter period of 3 or even 2 days has been shown to be effective [51].

According to the guidelines of the American Thoracic Society, lower airway infections due to normal potential pathogens, including H. influenzae and S.

aureus, should be treated for 7–10 days, whereas episodes caused by P. aerugi- nosa and Acinetobacter species should be treated for at least 14–21 days [52].

The guidelines are based on ‘expert’ opinion. There is only one randomised con-

trolled trial evaluating whether a short course of intravenous antimicrobial

therapy of 1 week is as effective as a prolonged treatment of equal or more than

2 weeks [53]. These investigators showed that there is no evidence to support an antibiotic course exceeding one week. A third approach for determining the duration of antibiotic therapy is the use of inflammation markers including C- reactive protein. Five prospective studies show that a course of appropriate antimicrobials of <1 week results in significant improvements of clinical, radi- ographic, and microbiological parameters [54-58].T here is no evidence to sup- port the superiority of a 2-week course of intravenous antibiotics over a 1-week course, which prompted us to implement a parenteral antibiotic policy of 5 days, followed by a careful evaluation of the patients’ clinical, radiographic, and microbiological parameters [59, 60].

Enteral Antimicrobials

The administration of enteral antimicrobials using a paste or gel and a suspen- sion into the throat and gut, respectively, is indicated so long as the patient is immunoparalyzed, i.e., at high risk of acquiring abnormal flora and subse- quently of developing an infection. SDD is generally given throughout the ICU treatment or, in practice, until extubation.

There is general consensus that long-term use of enteral polymyxin E/tobramycin/amphotericin B in the correct concentrations in throat and gut abolishes oropharyngeal and gastric carriage of the target PPM within a few days. Eradication of rectal carriage appears to depend on the presence of peri- stalsis and may vary until the patient produces faeces [61].

Topical Antimicrobials

Three days of topical application of polymyxin E/tobramycin/amphotericin B and/or vancomycin into wounds or tracheostoma or gastrostoma has been shown to eradicate the potential pathogens using daily sampling [48, 49].

Prevention of colonization/infection of wounds and stomas obviously requires the application of the topical antibiotics throughout the ICU treatment [49].

Endpoints of Antimicrobial Policies

A new antimicrobial agent launched by the pharmaceutical industry or a new

antibiotic policy implemented in the ICU should be assessed using four main

endpoints including morbidity, mortality, antimicrobial resistance, and costs

(Table 5). The pharmaceutical industry is not often able to provide that infor-

mation. If the superinfection rate associated with a particular antimicrobial is

known, that figure is often diluted by the number of all patients enrolled in all

studies, whether community, hospital-, or ICU-based, as denominator.

Superinfection rates are invariably higher in the critically ill patients requiring intensive care, including mechanical ventilation, compared with patients stay- ing on hospital wards. The more severely ill the patient population studied, the higher the superinfection rate. The mortality should be assessed following the immediate administration of the antimicrobial(s), as the delay of adequate ther- apy is associated with increased mortality [62, 63]. Immediate administration of an antimicrobial agent always implies an empirical decision in the absence of any knowledge of the causative micro-organism, although of course reasonable assumptions can be made depending upon the presentation of the disease [60].

It is highly likely that the patient carries “normal” potential pathogens in their admission flora if the patient was previously healthy (trauma, burn, acute liver failure, and pancreatitis patients). Patients with chronic underlying diseases, including alcoholism, chronic obstructive pulmonary disease, and diabetes, often import “abnormal” potential pathogens in their flora on admission.

Patients referred from other hospitals or from the wards are generally ill and may bring abnormal bacteria associated with the hospital ecology into the ICU.

Surveillance samples of throat and rectum taken at the time of admission may help in identifying the normal versus abnormal carrier state. These samples are also required to assess the impact of an antibiotic on the patient’s ecology, and to monitor secondary or supercarriage of resistant bacteria. This information is invariably missing for most new antibiotics or antibiotic policies. New antibi- otics are also recommended for 10 or more days and are always more expensive than the older antimicrobials that are often out of patent and inexpensive.

Table 5. Endpoints of antimicrobial policies (i) Efficacy: clinical endpoints

- reduction in infectious morbidity (superinfection)

- reduction in mortality following the immediate administration of empirical antimicro- bial

(ii) Safety: microbiological endpoints [using surveillance samples]

- impact on ecology: yeasts, Clostridium difficile (diarrhea)

- antimicrobial resistance: supercarriage of aerobic Gram-negative bacilli, methicillin- resistant Staphylococcus aureus, vancomycin-resistant enterococci

(iii) Costs

- duration: an antimicrobial course of <1 week is as good as that of ≥ 2 weeks

- is the newer more expensive antimicrobial superior than the older cheaper one in terms

of efficacy and safety

Our antimicrobial policy using the above criteria is shown in Chapter 18. A prospective, observational cohort study was performed over four years (1999–2003) to assess the efficacy, side-effects, and costs of this antibiotic poli- cy. Only critically ill children requiring 4 or more days of intensive care were included in the epidemiological descriptive study [64]. This study group repre- sents the sicker patients with longer pediatric ICU stays. Approximately two- thirds of pediatric ICU admissions did not meet the 4-day stay entry criterion for the study, and are not included in the denominator for infection rates. Short- stay patients have a low risk of developing secondary endogenous and exoge- nous infection, and we believe they should not be reported in the denominator of pediatric ICU infection rates. A total of 1,241 children were included in the study. There were 520 children with infections, an overall infection rate of 41.9%, viral infections accounted for 14.5% and bacterial/yeast infections for 33.0%. The incidence of blood stream infection and lower airway infection was 21.0 and 9.1 episodes per 1,000 patient-days; 13.3% of the children were infect- ed with a micro-organism acquired on the pediatricICU; 4.0% of admitted patients developed infections due to resistant micro-organisms. The mortality in the study group was 9.6%.

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