antibiotice in terapie intensiva

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601Indian Journal of Clinical Practice, Vol. 23, No. 10 March 2013

CRITICAL CARE

Antimicrobial Therapy in the Intensive Care Unit

MS KRISHNA SARIN*, M VADIVELAN**, CHANAVEERAPPA BAMMIGATTI**

ABSTRACT

Severe sepsis and septic shock in the intensive care unit (ICU) needs emergent coverage with empirical broad-spectrumantibiotics, with a commitment to de-escalation once the organism and its susceptibility to a particular antibiotic becomesknown. The dose and duration of antibiotic must be optimized according to standard guidelines to prevent emergence ofresistant pathogens. Strategies of using Procalcitonin measurements in guiding the duration of antibiotic treatment andaerosolized antibiotics are helpful in optimizing antibiotic usage. Eorts are needed to prevent emergence of antibioticresistance by pathogens, as the antibiotic pipeline is dwindling and the number of newly discovered multidrug-resistant (MDR)pathogens is increasing. Prevention of infection must be given top priority by strict adherence to asepsis measures.

Keywords: Septic shock, intensive care unit, procalcitonin, aerosolized antibiotics, multidrug-resistant pathogens

*Junior Resident**Assistant Professor, Dept. of Medicine

Jawaharlal Institute of Post Graduate Medical Educationand Research (JIPMER), PondicherryAddress for correspondenceDr M Vadivelan

Q.No.: E-2, JIPMER Quarters, JIPMER Campus, Dhanvantari NagarPondicherry - 605 006E-mail: [email protected]

The intensive care unit (ICU) is a place where

patients with complex medical problems arecrowded into a small area. The acute nature

of critically ill patients necessitates the use of broad-

spectrum antibiotics frequently.

Fever in a patient in the ICU must be considered

signicant when the body temperature is >38.3°C

(101°F) and a detailed evaluation must be carried out to

ascertain whether infection is present or not.1 A lower

threshold of fever must be used in immunocompromised

patients.

However, as many as 50% of ICU patients with

fever have no apparent infection. Fever is a sign of

inammation, not infection. Hence, noninfectious

causes of fever must be ruled out before subjecting

the patient to a number of costly and invasive

diagnostic procedures.

Noninfectious causes of fever in ICU

Â Postoperative fever: Fever on the rst day followingmajor surgery is reported in 15-40% of patients.2

Â Procedures: Hemodialysis, bronchoscopy, bloodtransfusions.

Â Endocrine disorders: Thyrotoxicosis, adrenal crisis.

Â Myocardial infarction, stroke and venous thrombo-embolism.

Â Drug fever: Common oending drugs are

cephalosporins, penicillins and amphotericin B andphenytoin.

Infectious causes of fever in ICU

Â Sinusitis Â Catheter-related bloodstream infection (CRBSI)

Â Ventilator-associated pneumonia (VAP)

Â Catheter-associated urinary tract infection (UTI)

Â Wound infections

SEPSIS WITHOUT AN OBVIOUS FOCUS

In critically ill patients, the source of infection may

not be apparent at the time of admission to the ICU.

In such patients, empirical antibiotics must be started

intravenously as early as possible within the rst

hour of recognition of severe sepsis and septic shock.

Each hour of delay will decrease the survival by 7.6%

approximately.3

A rough guide to the choice of empirical antibiotics

when the focus of infection is unknown is presented

in Table 1.4

Empirical coverage for methicillin-resistant

Staphylococcus aureus (MRSA) with vancomycin is

required in the following situations:


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602 Indian Journal of Clinical Practice, Vol. 23, No. 10 March 2013

CRITICAL CARE

Â Patients with indwelling vascular catheters

Â If patient has received quinolone prophylaxis

Â If the institution has a high incidence of MRSAinfections.

Â If there is a high prevalence of MRSA isolates inthe community.

Indications for empirical antifungal drugs are:

Â If the septic patient has been neutropenic for vedays or more

Â If the patient has had a long-term central venouscatheter

Â If the patient has been hospitalized in an ICU andreceived broad-spectrum antibiotics for a prolongedperiod.

Amphotericin B is the drug of choice for all life-threatening fungal infections and as empiricaltherapy in neutropenic patients with persistent fever.Fluconazole is used for treatment of candidiasis inpatients who are hemodynamically stable and arenot immunocompromised. The echinocandins (e.g.caspofungin) can be used for invasive candidiasis asthe drug provides improved coverage against allCandida species.

A combination of antibiotics is usually chosen forneutropenic sepsis and in patients with suspectedPseudomonas infections. The drugs which can be

used in combination are ceazidime or piperacillin-tazobactam or meropenem with an aminoglycoside.5 Indications for administering combination therapywith two drugs active against Pseudomonas are:

Â Neutropenic fever

Â Severe sepsis and septic shock

Â Presence of serious infections like pneumonia,endocarditis and meningitis.

All patients must receive the full loading dose ofeach antimicrobial irrespective of the renal function.

Subsequently, renal-modied dose of the drug can be

given.

SEPSIS WITH AN IDENTIFIED FOCUS OF

INFECTION

Ventilator-associated Pneumonia

The diagnosis of VAP is made on the basis of a new

inltrate in the chest X-ray with two of the following:

Â Fever

Â Leukocytosis

Â Purulent tracheal secretions

VAP can be classied as:

Â Early: If infection began within ve days aerhospital admission.

Â Late: If infection began more than ve days aeradmission.

Empirical therapy for early VAP is recommended usinga single agent which can be any one of the followingdrugs:6

Â Ceriaxone

Â Levooxacin/Ciprooxacin/Moxioxacin

Â Ampicillin + Sulbactam

Â Ertapenem

Combination therapy is advised for late VAP and when

VAP is suspected to be due to a multidrug-resistant(MDR) pathogen.6 The drugs used are:

Â Ceazidime/Cefepime

Â Imipenem/Meropenem

Â Piperacillin-Tazobactam + an Aminoglycoside/

Fluoroquinolone + Vancomycin/Linezolid.

Optimum duration of therapy for VAP is eight days.

Catheter-related Bloodstream Infections

The diagnosis of CRBSI depends on the demonstration,

by culture, of the same organism from the catheter

tip and blood culture. A colony count at least 3-foldgreater for blood obtained from the catheter hub

or a dierential time to positivity (DTP) of at least

two hours at the catheter hub also indicates CRBSI.7

The catheter must be removed in severe sepsis,

suppurative thrombophlebitis, endocarditis and

infections due to S. aureus , Pseudomonas aeruginosa ,

fungi or mycobacteria, and in a CRBSI that continues

despite 72 hours of antimicrobial therapy to which the

infecting microbes are susceptible.

Table 1. Empirical Therapy for Severe Sepsis with no

Obvious Focus

Clinical condition Antimicrobial regimens (IV therapy)

Immunocompetent

adult

Piperacillin-Tazobactam/Meropenem/

Cefepime ± VancomycinNeutropenia

(


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CRBSI is treated with the combination of a fourth-

generation cephalosporin/carbapenem plus vancomycin

to cover MRSA. An aminoglycoside is added if

Pseudomonas is suspected. The duration of therapy

depends on the infecting pathogen. Complicated

CRBSI (i.e., CRBSI-associated with suppurative

thrombophlebitis, endocarditis) requires at least

28 days of antibiotic therapy.

Catheter-associated UTIs

Catheter-associated UTIs are diagnosed when

bacteriuria (10³ colony forming units/ml) is associated

with symptoms compatible with UTI. Symptoms

include fever with rigors, ank pain, renal angle

tenderness, hematuria or pelvic discomfort.

These infections are oen polymicrobial and are caused

by MDR pathogens. Urine culture results are requiredto guide treatment. Catheter has to be replaced if it has

been in place for more than two weeks and if its use

cannot be discontinued.

The recommended duration of antimicrobial

treatment for patients with catheter-associated UTI

who have rapid resolution of symptoms is 7 days and

10-14 days for those with a delayed response,

regardless of whether the patient remains catheterized

or not.8

ANTIBIOTIC THERAPY DEPENDING ON THE SITE

OF INFECTION

Once the source of sepsis is known, the antimicrobial

therapy should be tailored according to the possible

infecting pathogens and their relative antibiotic

susceptibilities. A summary of the possible etiologic

agents according to the site of infection and the drug

that can be used is given in Table 2.9

TREATMENT OF MDR PATHOGENS

MDR pathogens are a real and constant threat in

the ICU environment. The six most common MDR

pathogens encompassed in the eponymous ‘ESKAPE’

Table 2. Antibiotic Therapy Depending on the Site of Infection

Site of infection Bacteria Suggested treatment

UTI

Severe acute pyelonephritis

E. coli

P. aeruginosa

Enterococcus species

Staphylococcus species

Ceftriaxone or Ceftazidime ± Aminoglycoside

Intra-abdominal sepsis E. coli

P. aeruginosa

Enterococcus species

Bacteroides species

Ertapenem

Piperacillin-Tazobactam

Third- or fourth-generation cephalosporin

(active against P. aeruginosa) + Metronidazole

Nosocomial pneumonia Enterobacteriaceae

P. aeruginosa

S. aureus

S. pneumoniae

H. infuenzae

β-lactam (active against P. aeruginosa) ±

Aminoglycoside ± Glycopeptide (vancomycin)

Pneumonia without risk factors for MDR

Pseudomonas

S. aureus

S. pneumoniae

H. infuenzae

Other gram-negative bacilli

Third-generation Cephalosporin ± Macrolide

Skin infections Streptococcus species

Staphylococcus species

Gram-negative bacilli

β-lactam + β-lactamase inhibitor


Carbapenem

CRBSI Staphylococcus species

Enterobacteriaceae

P. aeruginosa

Vancomycin + β-lactam with activity against

P. aeruginosa


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group are Enterococcus faecium, S. aureus, Klebsiella

pneumoniae, Acinetobacter species, P. aeruginosa and

the Enterobacter species.

Tables 3 and 4 summarize the treatment options for

various MDR pathogens.

NEWER CONCEPTS IN ANTIMICROBIAL THERAPY

Procalcitonin as a Biomarker in Sepsis

Procalcitonin is the best studied biomarker for guiding

antibiotic treatment duration in the hospital seing.

Procalcitonin dynamics within 72 hours aer onset of

sepsis may be correlated both with appropriateness

of the empirical antibiotic therapy and with overall

survival.10

Procalcitonin measurements integrated in clinical

algorithms have been shown to reduce the duration of

antibiotic courses by 25-65% in hospitalized and more

severely ill patients with CAP and sepsis.11

Pharmacokinetics in Drug-dosing Time/Concentration-dependent Killing

Antibiotics like b-lactams, quinolones and vancomycin

exert their microbicidal activity depending on the

duration for which the plasma drug levels remainabove the minimum inhibitory concentration (MIC).

An appropriate strategy is to administer these

antibiotics as a continuous infusion rather than as bolus

doses.

On the other hand, aminoglycosides exert their action

depending on the peak levels achieved in plasma. So,

the appropriate strategy will be to give the entire daily

dose as a single bolus injection.

The pharmacokinetics of antibiotics is modied in ICU

patients owing to the large daily uid balance, acute

changes in body weight, hypoalbuminemia, edemaand low hematocrit values that lead to a marked

change in elimination half-life, volume of distribution

and clearance. Sepsis increases capillary permeability

Table 3. Treatment Options for Resistant Gram-positive Bacteria

Drug Route of

administration

Activity against MRSA Activity against resistant

S. pneumoniae

Activity against vancomycin-

resistant Enterococci

Vancomycin IV only Yes Yes No

Daptomycin IV only Skin infection/Bloodstream infection No Yes

Linezolid IV or oral Pneumonia/Skin infection No Yes

Quinupristin-

Dalfupristin

IV only Yes No Yes, against E. faecium

Telavancin IV only Skin infection/Pneumonia Yes Yes

Tigecycline IV only Pneumonia/Skin infection Yes Yes

Ceftaroline IV only Pneumonia/Skin infection Yes No

Table 4. Treatment Options for Resistant Gram-negative Bacteria

Organism First-line therapy Second-line therapy

Empirical therapy

Monomicrobial infection Carbapenem

Tigecycline (not in UTIs) ±

Antipseudomonal agent


Colistin

Polymicrobial infection Carbapenem + Vancomycin

Tigecycline (not in UTIs) ±

Antipseudomonal agent

Piperacillin-Tazobactam + Vancomycin

Colistin + Vancomycin

Directed therapy

ESBL-producing Enterobacteriaceae Carbapenem


Tigecycline (not in UTIs)

Fluoroquinolone

Colistin

Carbapenemase-producing

Enterobacteriaceae

Tigecycline

Colistin

Fosfomycin (parenteral formulation)

MDR P. aeruginosa Meropenem Colistin


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with third space sequestration resulting in higherantibacterial drug clearances.

Multiple organ dysfunctions cause a decrease inantibacterial drug clearance. Hence, monitoring of

plasma drug concentrations needs to be performedwhenever possible because these concentrations aredicult to predict in critically ill patients.

Aerosolized Antibiotics

Intermient aerosolization of antibiotics into the

respiratory tract has been used in patients withP. aeruginosa pneumonia, particularly in the seing

of cystic brosis. Tobramycin and colistin have been

used in pneumonia caused by MDR Pseudomonas.

Recently, amikacin, nebulized with special devices has

been used for MDR gram-negative pneumonia that was

unresponsive to standard therapy.

ANTIMICROBIAL RESISTANCE AND ITS

IMPLICATIONS

MDR pathogens are most frequently encountered in

the ICU. The prime reason for the development of

antimicrobial resistance is antibiotic misuse. Irrational

antibiotic prescription for nondocumented infections

in stable patients, prolonged use of broad-spectrum

antibiotics without de-escalation, incorrect dosages

and dosing intervals and continuation of the antibiotic

course beyond the optimally recommended duration

contribute to the development of resistance. Practices

that promote optimization of antibiotic use in the ICU

are summarized in Table 5.12

The key point is to avoid antibiotic misuse by using

them only in patients with documented infections

except if the infections are life-threatening and

avoiding the treatment of asymptomatic colonization.

De-escalation of broad-spectrum antibiotics based on

clinical response and microbiological ndings is needed

to avoid the emergence of MDR pathogens.

Optimizing the duration of antimicrobial therapy

by following a protocol-guided discontinuation if

appropriate cultures are negative aer Day 3 and

prescribing the antibiotic course for the optimum

duration will help to reduce the emergence of

resistance. The optimum duration of antibiotic therapy

for the commonly encountered infections in the

ICU, according to the Infectious Diseases Society of

America (IDSA) guidelines is given in Table 6. Certain

practices may be helpful in controlling antibiotic

resistance.

Table 6. Predetermined duration of Antibiotic Therapy

based on the IDSA Guidelines

Site of infection Duration of

antibiotic

therapy (days)

Lung infection

CAP due to S. pneumoniae 8

VAP 8

VAP and immunodepression 14

Pneumonia due to Legionella pneumophila 21

Pneumonia with lung necrosis ≥28

Intra-abdominal infections

Community peritonitis


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Scheduled Changes in Antibiotic Therapy

Periodic changes in the antibiotic preference in treating

infections caused by the same pathogen (e.g., gram-

negative infections treated with a cephalosporin for

the rst six months and a uoroquinolone for the next6 months) may help to reduce the emergence of

resistance to either class.

Antibiotic Class Cycling

A class of antibiotic is withdrawn from use for a

dened time period and reintroduced at a later point

of time in an aempt to limit bacterial resistance to the

antimicrobial agent.

For any ICU, wrien protocols must be developed

based on the local ecology of microorganisms and their

paern of resistance. This is best done in consultation

with the Dept. of Microbiology. An infectious

disease specialist consultation helps in improving

the accuracy of the prescription of antimicrobial drugs.

PREVENTION OF INFECTIONS IN THE ICU

Simple measures to prevent infection and pathogencross-transmission assume signicance considering thehuge expenses incurred in terms of patient morbidityand mortality as well as the indirect costs involvedin treating a resistant infection. A summary of therecommendations made by the Centers for Disease

Control is given below:13

Prevention of Central Venous CatheterInfections

Â Educate personnel about catheter insertion and care.

Â Use chlorhexidine to prepare the insertion site.

Â Use maximal barrier precautions during catheterinsertion.

Â Consolidate insertion supplies (e.g., in an insertionkit or cart)

Â Use a checklist to enhance adherence to the bundle.

Â

Empower nurses to halt insertion if asepsis is breached.

Â Cleanse patients daily with chlorhexidine.

Â Ask daily: Is the catheter needed? Remove catheterif not needed or used.

Prevention of VAP

Â Elevate head end of bed to 30-45°.

Â Decontaminate oropharynx regularly withchlorhexidine.

Â Give ‘sedation vacation’ and assess readiness toextubate daily.

Â Use peptic ulcer disease prophylaxis.

Â Use deep-vein thrombosis prophylaxis (unless

contraindicated).

Prevention of UTIs

Â Place bladder catheters only when absolutelyneeded (e.g. to relieve obstruction), not solely forthe provider’s convenience.

Â Use aseptic technique for catheter insertion andurinary tract instrumentation.

Â Minimize manipulation or opening of drainagesystems.

Â Ask daily: Is the catheter needed? Remove catheter

if not needed.

Prevention of Surgical-site Infections

Â Choose a surgeon wisely.

Â Administer prophylactic antibiotics withinone hour before surgery; discontinue within24 hours.

Â Limit any hair removal to the time of surgery; useclippers or do not remove hair at all.

Â Prepare surgical site with chlorhexidine-alcohol.

Â Maintain normal perioperative blood glucose levels

(cardiac surgery patients).

Â Maintain perioperative normothermia (colorectalsurgery patients).

Prevention of Pathogen Cross-transmission

Cleanse hands with alcohol hand rub before and

aer all contacts with patients or their environments.

REFERENCES

1. O’Grady NP, Barie PS, Bartle JG, Bleck T, Carroll K, KalilAC, et al; American College of Critical Care Medicine;Infectious Diseases Society of America. Guidelinesfor evaluation of new fever in critically ill adultpatients: 2008 update from the American College ofCritical Care Medicine and the Infectious DiseasesSociety of America. Crit Care Med 2008;36(4): 1330-49.

2. Fry DE. Fever in the ICU. The ICU Book 2008; 39(3):716.

3. Dellinger RP, Levy MM, Carlet JM, Bion J, ParkerMM, Jaeschke R, et al; International Surviving Sepsis

Campaign Guidelines Commiee; American Associationof Critical-Care Nurses; American College of Chest

Physicians; American College of Emergency Physicians;


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Canadian Critical Care Society; European Society ofClinical Microbiology and Infectious Diseases; EuropeanSociety of Intensive Care Medicine; European RespiratorySociety; International Sepsis Forum; Japanese Associationfor Acute Medicine; Japanese Society of Intensive Care

Medicine; Society of Critical Care Medicine; Society ofHospital Medicine; Surgical Infection Society; WorldFederation of Societies of Intensive and CriticalCare Medicine. Surviving Sepsis Campaign:international guidelines for management of severesepsis and septic shock: 2008. Crit Care Med 2008;36(1):296-327.

4. Munford RS. Severe sepsis and septic shock. In:Harrison’s Principles of Internal Medicine. Volume 2,2012;271(18):p.2229.

5. Kanj SS, Kanafani ZA. Current concepts inantimicrobial therapy against resistant gram-negativeorganisms: extended-spectrum beta-lactamase-

producing Enterobacteriaceae, carbapenem-resistantEnterobacteriaceae, and multidrug-resistant Pseudomonasaeruginosa. Mayo Clin Proc 2011;86(3):250-9.

6. American Thoracic Society; Infectious Diseases Society ofAmerica. Guidelines for the management of adults withhospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med2005;171(4):388-416.

7. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P,O’Grady NP, et al. Clinical practice guidelines for thediagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious DiseasesSociety of America. Clin Infect Dis 2009;49(1):1-45.

8. Hooton TM, Bradley SF, Cardenas DD, Colgan R,Geerlings SE, Rice JC, et al; Infectious Diseases Societyof America. Diagnosis, prevention, and treatment ofcatheter-associated urinary tract infection in adults:2009 International Clinical Practice Guidelines from theInfectious Diseases Society of America. Clin Infect Dis2010;50(5):625-63.

9. Textoris J, Wiramus S, Martin C, Leone M. Overviewof antimicrobial therapy in intensive care units. ExpertRev Anti Infect Ther 2011;9(1):97-109.

10. Schuetz P, Albrich W, Mueller B. Procalcitonin fordiagnosis of infection and guide to antibiotic decisions:past, present and future. BMC Med 2011;9:107.

11. Harbarth S, Haustein T. Year in review 2009: CriticalCare - infection. Crit Care 2010;14(6):240.

12. Kollef MH. Optimizing antibiotic therapy in the intensivecare unit seing. Crit Care 2001;5(4):189-95.

13. Robert A. Weinstein. Health Care-Associated Infections.Harrison’s Principles of Internal Medicine (Volume 1);131(18):1114.

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antibiotice in terapie intensiva

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