Antibiotic use in an Intensive care setting.

Dr.(Mrs.) Arundhati G. Diwan MD *, Dr. Jignesh Shah MD, DNB, EDIC **, Dr. Sachin A. Adukia MBBS ***

* Professor and Head, Dept. of Internal Medicine- Bharati hospital and Research Centre (BHRC), Pune **Intensivist and Assistant Professor, Dept. of Anaeathesia, BHRC, Pune.

***Resident, Second year- Dept. of Medicine, BHRC, Pune.

A decade earlier antibiotic resistance was emerging as

a growing threat to medical therapeutics. We always relied on

the stream of higher more powerful antibiotics to flow out of

major pharmaceutical companies till the day has come that this

stream is reduced to a trickle and almost dried up. Today the

Indian physician faces a plethora of resistant microbes which

are spilling out of the intensive care into the community. A few

examples are multidrug resistant (MDR)-TB, Methicillin

resistant Staph. Aures (MRSA), Vancomycin resistant Staph.

Aures(VRSA), the extended spectrum beta lactamase(ESBL)

bacteria and more recently the New Delhi Metallo beta

lactamase-1 (NDM-1) producing bacteria.

The Extended Prevalence of Infection in Intensive Care (EPIC

II) study concluded that infections are common in patients in

contemporary ICUs, and risk of infection increases with

duration of ICU stay(1).Closer to home, a recent study on

antibiotic use in a tertiary care centre in an Indian city reveals

that approximately Rs.39000 is spent on antimicrobial therapy

alone to make one patient of disease from infection requiring

ICU survive(2). It implies that infections can cost the patient

money and life due to subjective irrational dispensing of

antibiotics in ICU.

CLASSIFICATION OF ANTIBIOTICS(3)

Cell wall synthesis inhibitors

Beta-lactams -penicillins,cephalosporins,

aztreonam , carbapenems

Poly-peptides -bacitracin , vancomycin,

cycloserine

Protein synthesis inhibitors

Bacterostatic :Tetracyclines, Macrolides,

Chloramphenicol, Clindamycin, Linezolid

Bacteriocidal: Aminoglycosides

Antimetabolite- Sulfonamides, Trimethoprim

Topoisomerase inhibitors- quinolones

Membranotoxic compound – Polymyxin,

daptomycin

RNA polymerase inhibitors- rifampin,

rifabutin.

PROPHYLACTIC ANTIBIOTICS:-

1. Antibiotic prophylaxis is not required in percutaneous

arterial and central venous catheters for insertion or while

indwelling. Same applies for indwelling drains as it increases

the risk of later infection by MDR pathogen (4).

2. Selective digestive decontamination (SDD) with topical and

parenteral antibiotics decreases the incidence of respiratory

tract infections by 65% and death. However prolonged

prophylaxis is associated with postoperative pneumonia,(5)

catheter sepsis and catheter-related blood stream infection(6) and

infection by MRSA(4). Risk of Clostridium difficile-related

disease (antibiotic-assoiated colitis) goes up fivefold(7).

3. In hepatic cirrhosis with portal hypertension and variceal

hemorrhage antibiotic prophylaxis is of clear benefit(8). It

reduces risk of infection, recurrent hemorrhage and death (9).

4. Systemic antibiotic prophylaxis shows reduction in

nosocomial pneumonia and also a 20% reduction in overall

mortality(10).

EMPIRICAL ANTIBIOTICS:

Factors to be considered when selecting empiric antimicrobial

therapy(11) :

1. Select empiric monotherapy based on coverage of

predictable pathogens as per focus (organ) of infection

(blood/urine/intra-abdominal).

2. Select antibiotic with low resistance potential (locally).

3. Select antibiotic with a good safety profile (eg. least

nephrotoxic).

Combination therapy is more appropriate for those prone to

MDR pathogens (table 1). Therefore, initial coverage should

include agents from different classes. Gram-negative coverage

typically involves a β-lactam, quinolone or aminoglycoside(11).

For patients with severe sepsis, intravenous antibiotic therapy

should be started within the first hour of recognition of severe

sepsis, after taking appropriate culture samples(12).

Table1. Risk Factors for MDR Organisms(13):

Exposure

History of MDRO(multidrug resistant organisms)

Colonization pressure (facility rates of MDRO

infection/colonization)

Recent antibiotics

Recent hospitalization

Comorbidity/Dependency (need for contact care)

Dialysis

“Fertile Ground” For Bacterial Proliferation

Wounds

Indwelling devices

Dental plaque

Structural lung disease (bronchiectasis, COPD)

THERAPEUTIC USE ANTIBIOTICS:

Pneumonia:-

1. Community acquired pneumonia:- Penicillins remain

effective despite increasing resistance of S. pneumoniae. They

are given for a period of 10 days, or for 14-21 days in cases

caused by Legionella, S. Aureus or gram-negative enteric

bacilli.

2. Hospital acquired pneumonia and ventilator associated

pnenmonia:- For infections developing within four days of

hospital admission, in patients with no other risk factors for

resistant pathogens (Table 2), appropriate agents are co-

amoxiclav, cefuroxime or a fluoroquinolone. For late-onset

cases and those with previous antibiotic exposure or other risk

factors, treatment with an antipseudomonal beta-lactam

(piperacillin / tazobactam, ceftazidime or a carbapenem) or an

antipseudomonal fluoroquinolone (ciprofloxacin/ levofloxacin)

is recommended. Addition of a glycopeptide or linezolid should

be considered if the risk of MRSA is judged to be high. Short

courses of antibiotics appear to be be as effective as longer

ones, and may reduce the risk of bacterial resistance(14).

Table 2. Risk factors for multidrug-resistant

pathogens causing hospital-acquired pneumonia

(HAP), healthcare-associated pneumonia

(HCAP), and Ventilator -associated pneumonia

(VAP)(15) Antimicrobial therapy in preceding 90 d

Current hospitalization of 5 d or more

High frequency of antibiotic resistance in the

community or

in the specific hospital unit

Presence of risk factors for HCAP:

Hospitalization for 2 d or more in the preceding 90 d

Residence in a nursing home or extended care facility

Home infusion therapy (including antibiotics)

Chronic dialysis within 30 d

Home wound care

Family member with multidrug-resistant pathogen

Immunosuppressive disease and/or therapy

Selective decontamination of the digestivetract (SDD):-

Non-absorbable antibiotics, commonly a combination of

polymyxin, amphotericinB and aminoglycoside, are applied

via nasogastric tube and, as a paste, to the oropharynx.

Systemic antibiotics, cefotaxime and ciprofloxacin, may be

added during the first four days in the ICU to prevent early

infections(14).

Pulmonary aspiration:-

Antibiotic treatment should be restricted to patients with

clinical evidence of infection, and should follow standard

guidelines for community or hospital-acquired pneumonia(14).

Complicated intra-abdominal sepsis:

Empirical treatment of community-acquired infections includes

narrow spectrum agents eg metronidazole plus cephalosporin

(cefuroxime)/ fluoroquinolone (ciprofloxacin). Severe

infections or in immunosuppressed hosts warrant broader

spectrum treatment with carbapenems, piperacillin/ tazobactam,

or a combination of metronidazole and a 3rd or 4th-gen.

cephalosporin or Tigecycline. Hospital-acquired infections

involve resistant organisms such as Enterobacteriaceae.

Commonly used regimens incorporate an aminoglycoside plus

an anti-pseudomonal b-lactam such as piperacillin/ tazobactam.

3rd and 4th-generation cephalosporins, carbapenems, and

extended-spectrum penicillins such as piperacillin/ tazobactam

are all effective. Addition of glycopeptide should be considered

when there is a high risk of infection with MRSA. Five to seven

days treatment is usually adequate (14).

Meningitis and meningococcal septicaemia: Community

acquired meningitis involves S. pneumoniae and

N.meningitides. with the occasional L. monocytogenes, S.

aureus, M.tuberculosis and E. coli. Lumbar puncture should not

delay administration of antibiotics because this may reduce the

chances of survival. Initial treatment is intravenous

cefotaxime, 2 g 6-hourly, or ceftriaxone, 2 g 12-hourly.

Therapy should further be guided by gram staining of CSF or

by culture reports(14).

Methicillin-resistant S. aureus (MRSA): Glycopeptides or

linezolid are the agents of choice for MRSA bacteraemia and

pneumonia, and for skin and soft tissue infections where the

risk of bacteraemia is high. Minimum duration of treatment is

14 days for bacteraemia (14).

It must be noted that the eventual choice of antibiotics has to be

guided by knowledge of institutional antibiograms and

susceptibility patterns.

Table 3: Empiric Antibiotic Selection in suspect

causatives(16). Organism Antibiotic Alternative

Gram-positive organisms

Staphylococci

aureus

Cefazolin or

Vancomycin

Linezolid

Coagulase-

negative

staphylococci

Vancomycin Linezolid…….

S.pneumoniae Ceftriaxone Moxifloxacin

Enterococcus

faecalis

Ampicillin +/-

Gentamicin

Vancomycin +/-

Gentamicin

Enterococcus

faecium

Linezolid Quinupristin

/ dalfopristin

Gram-negative organisms

Serratia Piperacillin/tazobacta

m / Gentamicin

β-lactam /

Ciprofloxacin

or

Ciprofloxacin /

aminoglycoside

Pseudomonas

aeruginosa

Piperacillin /

tazobactam /

Tobramycin

Acinetobacter Cefepime

/Gentamicin

Citrobacter Cefepime

/Gentamicin

Enterobacter Piperacillin/tazobacta

m / Gentamicin

E. coli (non-ESBL

isolate)

Cefazolin Gentamicin

Klebsiella (non-

ESBL isolate)

Cefazolin Gentamicin or

Quinolone

Haemophilus

influenzae

Azithromycin Cefuroxime

E. coli or

Klebsiella (ESBL

producer)

Meropenem

--

Stenotrophomonas

maltophilia

Trimethoprim/sulfa

methoxazole

Ticarcillin /

clavulanic acid

ALTERATIONS IN PHARMACOKINETICS (PK) AND

PHARMACODYNAMICS (PD) IN A CRITICALLY ILL

PATIENT (17):-

Different antibiotic classes have been shown to have different

kill characteristics on bacteria (Fig. 1 and Table 4).

Y axis Cmax/MIC

T >MIC

================ MIC

X Axis Fig. 1:- X Axis- time in hours; Y Axis- concentration (mg/dl).

PK and PD parameters of antibiotics on a concentration vs. time curve.

Key: T >MIC = Time for which a drug’s plasma concentration remains

above the minimum inhibitory concentration (MIC) for a dosing

period; Cmax/MIC, the ratio of the maximum plasma antibiotic

concentration (Cmax) to MIC; AUC/MIC, the ratio of the area under the

concentration time curve during a 24-hour period (AUC0–24) to MIC.

(Adapted from Pharmacokinetic issues for antibiotics in the critically

ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)

Table 4:- Antibiotics with pharmacodynamic kill

characteristics(17):- Time-dependent Concentration-

dependent

Concentration-

dependent with

time-dependence

β-lactams

Carbapenems

Linezolid

Erythromycin

Clarithromycin

Lincosamides

Aminoglycosides

Metronidazole

Fluoroquinolones

Telithromycin

Daptomycin

Quinupristin-

dalfopristin

Fluoroquinolones

Aminoglycosides

Azithromycin

Tetracyclines

Glycopeptides

Tigecycline

Quinupristin-

dalfopristin

Linezolid

Changes in Volume of distribution (Vd):- Endotoxins result

in vasoconstriction or vasodilatation with maldistribution of

blood flow, endothelial damage and increased capillary

permeability. This capillary leak would increase the Vd of

hydrophilic drugs which decreases their plasma drug

concentration. Vd is also increased by mechanical ventilation,

significant burn injuries, hypoalbuminaemia (increased

capillary leakage) extracorporeal circuits (e.g., plasma

exchange, cardiopulmonary bypass), postsurgical drains.

Lipophilic drugs have a large Vd because of their partitioning

into adipose tissue, and as such the increased Vd that results

from third-spacing is likely to cause insignificant increases in

drug Vd(17).

Changes in Antibiotic Half-Life: Drug elimination half-life

(T1/2) is represented by the equation:

T 1/2 = 0.693 x Vd/ CL

Standard initial management of hypotension in critically ill

patients is administration of intravenous fluids (to increase

Vd). When hypotension persists, vasopressor agents are added

(to increase peripheral vascular resistance which reduces renal

perfusion and hence CL= creatinine clearance). Dose

adjustment for hydrophilic antibiotics can be guided by

measures of creatinine clearance whereas equations such as the

Cockroft-Gault and Modified Diet in Renal Disease equations

are likely to be unreliable and, if possible, should not be

substituted for urinary creatinine clearance data(17).

Hypoalbuminemia: Protein binding influence the Vd and CL

of many antibiotics. A notable example is of ceftriaxone, which

is 95% bound to albumin in normal ward patients. In

hypoalbuminemic states, as common in critically ill patients,

this can result in a higher unbound concentration that has a

100% increased CL and 90% greater Vd(17).

Development of End-Organ Dysfunction: Multiple organ

dysfunction syndrome, which includes renal and/or hepatic

dysfunction results in decreased antibiotic CL, prolonged T1/2,

and potential toxicity from elevated antibiotic concentrations

and/or accumulation of metabolites(17).

Fig 2 identifies the above pathophysiological effects.

Fig 2. Schematic representation of the basic pathophysiological

changes that occur during sepsis and their subsequent pharmacokinetic

effects; Key-CL creatinine clearance; Vd, volume of distribution.

(Adapted from Pharmacokinetic issues for antibiotics in the critically

ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)

General Dosing Consideration: Selection of effective dosing

regimens translates into effective antibiotic therapy in the

critically ill. Table 5(vide infra) proposes some general dosing

recommendations to this end with consideration especially for

the altered renal function.

ANTIBIOTIC RESIISTANCE (18):

Mechanisms of drug resistance:-

First, via acquisition by bacteria of genes encoding enzymes,

such as beta-lactamases, that destroy the antibacterial agent

Concentration dependent

e.g. Aminoglycosides

AUC/MIC

e.g. fluoroquinolones

Time-dependant

e.g. β-lactams

Table 5 Broad guidelines that can be used for antibiotic dosing adjustment in critically ill patients (17)

Antibiotic Class

Suggested Dosing Adjustment for Critically Ill Patients

Normal Renal Function

Moderate to Severe Renal Dysfunction

Comments

Aminoglycosides Use high doses (e.g., gentamicin 7 mg/kg) where

possible to target Cmax:MIC ratio of 10

Use high doses where possible and monitor Cmin

thereafter (36 to 48 hourly extended interval dosing

acceptable); dosing can be guided by MIC data if

available

β-lactams/

Carbapenems

Consider extended or continuous infusion or

more frequent dosing to ensure T > MIC;

If intermitted dosing used, dosing can occur at

reduced dose or frequency (not both); err toward

larger doses as β-lactams have large therapeutic

window.

Glycopeptides Dosing at 30–40 mg/kg/day (vancomycin), may be

increased according to Cmin plasma concentrations (aim

for 15–20 mg/L)

High dosing on day 1 may be required to ensure

adequate distribution; dose adjustments should

occur according to Cmin

Fluoroquinolones Doses that achieve high Cmax:MIC ratio should be

targeted (e.g. ciprofloxacin 1200 mg/day); levofloxacin

may require 500 mg 12-hourly in some patients with

high creatinine clearance; where high doses used,

monitor for toxicity (seizures)

Dose adjustment is required in renal impairment for

levofloxacin, gatifloxacin and ciprofloxacin

Tigecycline 100 mg loading dose then 50 mg 12 hourly No dose adjustment required in renal failure or

dialysisa

Linezolid 600 mg 12 hourly No dose adjustment required in renal failure or

dialysis

Colistin Use 5 mg/kg/day of colistin base (75,000 international

units/kg/day colistimethate sodium)b intravenously in 3

divided doses

Reduce dose or frequency (not both)

MIC, minimum inhibitory concentration; Cmax, maximum concentration; Cmin, minimum concentration.

a-if severe cholestasis present then tigecycline should be dosed with 50-mg loading dose, then 25 mg 12 hourly;

b-1 mg colistimethate sodium is equivalent to 12,500 international units. (Adapted from Pharmacokinetic issues for antibiotics in the critically ill patient - Critical Care Medicine 2009 Vol. 37, No. 3.)

before it can have an effect (e.g., erythromycin ribosomal

methylase in staphylococci).

Second, acquisition of efflux pumps that extrude the

antibacterial agent from the cell before it can reach its

target site and exert its effect (efflux of fluoroquinolones in

S aureus).

Third, by acquiring several genes for a metabolic pathway

which produces altered bacterial cell walls that no longer

contain the binding site of the antimicrobial agent or

acquiring mutations that limit access of antimicrobial

agents to the intracellular target site via downregulation of

porin genes(e.g., OmpF in E coli).

Through genetic exchange mechanisms including

transformation, conjugation, or transduction, many bacteria

become resistant to multiple classes of antibacterial agents,

and are labeled as multidrug resistant (defined as resistance

to 3 or more antibacterial drug classes).

Highlighted below are select examples of resistance

acquisition and identification with treatment options

amongst commom resistant ICU setting pathogens.

Methicillin-resistant S. aureus (MRSA): has acquired

genes for generation of PBP’2 (Penicillin binding protein-

2) which does not bind to any β lactam antibiotic making it

resistant to all penicillins, cephalosporins and

carbapenems.

MRSA can be identified on culture report by looking at

resistance to methicilin, oxacillin or cefoxitin.

Treatment options include glycopeptides like vancomycin

& teicoplanin, linezolid, Daptomycin, Quinopristin-

Dalfopristin and Tigecycline(19).

Multiresistant gram-negativee nterobacteriaceae- Those causing HAI include E.Coli, Klebsiella and Proteus.

They produce β lactamases to defend themselves against β

lactam antibiotics.

Three such β lactamases are TEM-1, AmpC and ESBL’s.

1) TEM-1 is plasmid encoded and confers absolute

resistance to ampicillin and amoxicillin

2) AmpC is chromosomally encoded and inducible. They

confer resistance to penicillin, first generation

cephalosporins. Mutant AmpC are resistant to β lactams, β

lactamase inhibitor (BL-BLI) combinations but are

susceptible to carbapenems.

3) ESBL-is plasmid encoded. They confer resistance to all

BL-BLI’s. ESBL strains are resistant to many other non β

lactam antibiotics through plasmid mediated resistance.

Carbapenem resistance is also growing amongst ESBL

organisms.

Microbiological identification is by looking at the activity

of extended-spectrum beta-lactams, including cefotaxime

and ceftazidime alone and in presence of clavulinic acid.

For ESBL producers activity is restored in the presence of

clavulanic acid.

Treatment is carbapenems – Meropenem/ Imipenem.

For Carbapenemase producing organisms, options are

Colistin, Polymixixn B, Tigecycline.

ESBL producers are often resistant to aminoglycosides,

fluoroquinolones, and trimethoprim-sulfamethoxazole.

They must be reported as resistant to all penicillins,

cephalosporins (but not cefoxitin or cefotetan), and

aztreonam regardless of the in vitro result(19).

P. aeruginosa: is intrinsically resistant to narrow-spectrum

penicillins, first- and second-generation cephalosporins,

trimethoprim, and sulfonamides.

It has a characteristic grape-like odour and contains the

pigment pyocyanin, imparting a bluish-green color on

culture media.

The antipseudomonal agents include extended-spectrum

penicillins, such as ticarcillin and piperacillin; extended -

spectrum cephalosporins, such as ceftazidime and

cefepime; carbapenems; aminoglycosides; and

fluoroquinolones. However, P. aeruginosa isolates that are

resistant to one or more of these agents, particularly

aminoglycoside and fluroquinolones(19).

Acinetobacter spp. Treatment is according to local

sensitivity patterns- empirical treatment will be

carbapenems. For carbapenem resistant strains colistin or

polymyxin B or tigecyline are alternatives(19).

Clostridium difficile- Treatment is stopping the causative

antibiotic if possible and administration of anticlostridial

antibiotic.The agent of choice of oral metronidazole .Oral

Vancomycin is an alternative agent(19).

Vancomycin-resistant enterococci- Because of altered PBP (penicillin binding protein)

enterococcus are inherently resistant to cephalosporins,

Some enterococci have become resistant to vancomycin

due to change in peptide side chain. These vancomycin

resistant enterococci (VRE) infections are harder to treat

because of their antibiotic resistance.

Treatment options for VRE are limited and include

Linezolid, Daptomycin, tigecycline and Quinopristin –

Dalfopristin(19).

ANTIMICROBIAL STEWARDSHIP (20):

It is the rational, systematic approach to the use of

antimicrobial agents in order to achieve optimal outcomes.

Recommendations by Infectious Disease Society of

America/ Society developing an institutional programme to

enhance stewardship involves a close working between

several members.

a. Core committee;

1. Infectious disease physician,

2. Clinical pharmacist with infectious disease

training,

3. Health care epidemiologist,

4. Clinical microbiologist,

b. Close collaboration with the hospital infection

prevention and control programme and the pharmacy and

therapeutics committee.

c. Support and collaboration of;

Hospital administration,

Quality assurance and patient safety programs,

d. Negotiate for adequate authority for outcomes;

e. Hospital administrative support for necessary

infrastructure;

f. Monitoring of the impact and outcomes.

When antibiotic usage is mandatory following guidelines

are recommended;

a. Risk stratification of the patient is done;

1. Patient type 1 (Community-acquired infection).

2. Patient type 2 ( Health-care infection)

3. Patient type 3 (Nosocomial infection)

b. Establish the common microbial flora and antibiotic

susceptibility prevalent in the area of the hospital regarding

the site of infection.

c. The prevalent data may be indicative of the trends

prevalent for the last approximately 6 months collected by

the clinical microbiologist updated at regular fixed

intervals or modified on priority basis should an outbreak

is likely o occur.

d. Depending on the clinical condition of the patient, site/

source of infection and laboratory parameters empirical

antibiotic is selected, awaiting culture and antibiotic

sensitivity report is available.

e. Once antibiotic sensitivity report is available, empirical

antibiotics if sensitive, then they are continued, otherwise

specific antimicrobial therapy is commenced as per culture

sensitivity report.

f. De-escalation or stopping of the antibiotics are done

onceclinical and laboratory parameters show recovery

g. Escalation of therapy is considered if MRSA, ESBL,

VRE or Carbapenemase producing organism or add

antifungals if fungal isolates are obtained(20).

PREVENTIVE STRATEGIES AGAINST

ANTIBIOTIC RESISTANCE (21) :

These include interventions aimed at improving antibiotic

use such as antibiotic rotation, antibiotic restriction, de-

escalation therapy. Area-specific therapy( i.e. according to

local prevalence of pathogens) and combination therapy

(discussed above) are other easily applicable strategies.

Contact precautions(19) is the most often overlooked

strategy to aid this cause. Standard precautions include:-

1. Hand hygiene-Hands must be cleansed before and

after every patient contact

2. Appropriate use of gloves, aprons & PPE when

exposure to body secretions or blood is considered

possible.

3. Appropriate handling and disposal of waste and

sharps.

4. Appropriate handling and management of clean &

soiled linens

5. Isolation precautions for certain infections

6. Terminal disinfection and decontamination of

healthcare equipments

Antibiotic rotation: involves withdrawal a class of

antibiotics or a specific antibiotic drug from use for a

defined time period and reintroduced at a later point in

time in an attempt to limit bacterial resistance to the cycled

antimicrobial agents(21).

De-escalation: of antibiotic therapy is a strategy to balance

the need to provide adequate initial antibiotic treatment of

high-risk patients with the avoidance of unnecessary

antibiotic utilization, which promotes resistance. Risk

stratification according to Table 1(13) should be employed

and those at high risk for infection with antibiotic-resistant

bacteria should be treated initially with a combination of

antibiotics providing coverage for the most likely

pathogens to be encountered in that specific intensive care

unit/clinical setting. Therapy should be modified once the

agent of infection is identified or discontinued altogether if

the diagnosis of infection becomes unlikely(21).

Restricting the hospital formulary (Antibiotic

restriction) : for use of certain antibiotics or classes of

antibiotics reduces the adverse drug reactions from the

restricted drug. This approach is generally applied to drugs

with broad spectrums of action (such as imipenem), where

antibiotic resistance emerges rapidly (as with third-

generation cephalosporins) and where toxicity is readily

identified. It has been difficult to demonstrate that

restricting hospital formularies is effective in curbing the

emergence of resistance or improving antimicrobial

efficacy. However, the restrictions have been successful in

outbreaks of infection with antibiotic- resistant bacteria,

particularly in conjunction with infection control practices

and antibiotic educational activities(21).

REFERENCES: 1. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD,

Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K; EPIC II

Group of Investigators. International study of the prevalence and

outcomes of infection in intensive care units. JAMA. 2009 Dec 2;

302(21):2323-9.

2. Sanjeev V Mangrulkar, Shubhalakhmi Mangrulkar, Pushkar Khair,

Anjali Phalke. Antibiotic Use in the Intensive Care Unit- JAPI

April 2012 • VOL. 60

3. Goodman and Gilman's The Pharmacological Basis of Therapeutics: Digital Edition, 11th Edition Edited by Laurence L Brunton PhD,

John S Lazo PhD, Keith Parker MD PhD, Iain Buxton DPh, and

Donald Blumenthal PhD. Published by The McGraw-Hill Companies, Inc., New York, NY, 2006. ISBN 0-07-146804-8

4. Manian FA, Meyer PL, Setzer J, Senkel D. Surgical site infections

associated with methicillin-resistant Staphylococcus aureus: do

postoperative factors play a role? Clin Infect Dis 2003;36:863-868

5. Fukatsu K, Saito H, Matsuda T, et al. Influences of type and

duration of antimicrobial prophylaxis on an outbreak of methicillin-

resistant Staphylococcus aureus and on the incidence of wound

infection. Arch Surg 1997;132:1320-1325.

6. Namias N, Harvill S, Ball S, et al. Cost and morbidity associated

with antibiotic prophylaxis in the ICU. J Am Coll Surg

1999;188:225-230.

7. Kreisel D, Savel TG, Silver AL, Cunningham JD. Surgical antibiotic

prophylaxis and Clostridium difficile toxin positivity. Arch Surg

1995;130:989-993

8. Barie PS. Surf’s up at evidence beach. Surg Infect 2004;5:227-228

(Editorial).

9. Soares-Weiser K, Brezis M, Tur-Kaspa R, et al. Antibiotic

prophylaxis of bacterial infections in cirrhotic inpatients: A meta-

analysis of randomized controlled trials. Scand J Gastroenterol

2003; 38:193-200.

10. Liberati A, D’Amico R, Pifferi S, Telaro E. Antibiotic prophylaxis

in intensive care units: Meta-analyses versus clinical practice.

Intensive Care Med 2000;26 (Suppl 1):S38-S44.2000.

11. Burke A. Cunha, MD, MACP. Sepsis And Septicshock:

Selection Of Empiric Antimicrobialtherapy. Crit Care Clin

24 (2008) 313334 12. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign

guidelines for management of severe sepsis and septic shock. Crit

Care Med 2004; 32:858-73. 13. Drinka P., Niederman M.S., El-Solh A.A., Crnich C.J. Assessment

of Risk Factors for Multi-Drug Resistant Organisms to Guide

Empiric Antibiotic Selection in Long Term Care: A Dilemma (2011) Journal of the American Medical Directors

Association, 12 (5), pp. 321-325.

14. NA Watson, M Denton .Antibiotic prescribing in critical care: specific indications. Journal of the Intensive Care Society-Volume

9, Number 1, April 2008.31-36

15. Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and Healthcare-associated PneumoniaAm J

Respir Crit Care Med Vol 171. pp 388–416, 2005.

16. Empiric antibiotic use in critically ill patients [Internet] Approved 5/08/2007 Available from: http://www.surgicalcriticalcare.net/

Guidelines /AntibioticProphylaxisinSurgery2012.pdf

17. Jason A. Roberts, B Pharm (Hons); Jeffrey Lipman, FJFICM, MD. Pharmacokinetic issues for antibiotics in the critically ill patient.

Society of Critical Care Medicine and Lippincott Williams &

Wilkins Crit Care Med 2009 Vol. 37, No. 3 18. Fred C. Tenover, PhD; Mechanisms of Antimicrobial Resistance in

Bacteria. American Journal of Medicine (2006) Vol 119 (6A), S3–

S10

19. The Sanford Guide to Antimicrobial Therapy (2011) D. Gilbert, R.

Moellering, G. Eliopoulis, M. Saag, H. Chambers, (Antimicrobial

Therapy). ISBN 1930808658

20. A Bhagwati. Guidelines for Antibiotic Usage in Common Situations. A supplement to JAPI December 2010 - vol. 58.49-50

21. Marin H Kollef. Optimizing antibiotic therapy in the intensive care

unit setting. Critical Care 2001, 5:189–195.