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Antibiotic use in an Intensive care setting.
Dr.(Mrs.) Arundhati G. Diwan MD *, Dr. Jignesh Shah MD, DNB, EDIC **, Dr. Sac...
2. Hospital acquired pneumonia and ventilator associated
pnenmonia:- For infections developing within four days of
hospita...
ALTERATIONS IN PHARMACOKINETICS (PK) AND
PHARMACODYNAMICS (PD) IN A CRITICALLY ILL
PATIENT (17)
:-
Different antibiotic cl...
Table 5 Broad guidelines that can be used for antibiotic dosing adjustment in critically ill patients (17)
Antibiotic Clas...
3) ESBL-is plasmid encoded. They confer resistance to all
BL-BLI’s. ESBL strains are resistant to many other non β
lactam ...
local prevalence of pathogens) and combination therapy
(discussed above) are other easily applicable strategies.
Contact p...
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Antibiotic use in an intensive care setting iacm, medicine update 2012

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Antibiotic use in an intensive care setting iacm, medicine update 2012

  1. 1. 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. 2. 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
  3. 3. 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
  4. 4. 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.
  5. 5. 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
  6. 6. 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.

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