Combating Drug Resistance in The Intensive Care Unit (ICU)

COMBATING DRUG RESISTANCE IN THE INTENSIVE

CARE UNIT (ICU)

Review Article

INTRODUCTION

The battle for supremacy between man and microbecontinues to play itself out in the ICU’s of this world.Everyone has an opinion on what is to be done and whatshould be done yet when it comes to putting it into practicethey still automatically do what they have been doing foryears. One should remember that effective anti- microbialsare developed tardily over many years but thedevelopment of drug resistance can be brought about quiterapidly. Research shows that the major faults for theappearance of resistant microbes lies in many irrationalpractices that can be addressed if there is a will to do so.

To understand the development of resistance thedifference between carriage of abnormal flora and theirovergrowth needs to be appreciated. Whereas carriage isthe persistence of abnormal flora in the throat or gut ,overgrowth implies their presence in high concentrationsusually >105 colony forming units of PPM/mL of saliva orper gram faeces. Overgrowth guarantees increasedspontaneous mutation leading to polyclonality andantibiotic resistance. The patient then becomes a reservoirof resistant organisms and at risk for endogenousinfections. Further overgrowth promotes disseminationthroughout the ICU. About 33% of patients develop denovo resistance whereas another third acquire resistantorganisms following transmission via hands of health careworkers and the rest import the organisms in theiradmission flora [1].

It should be made clear that healthy individuals do notbecome sustained carriers of abnormal microorganisms. Ithas been recently learnt that illness severity is the mostimportant risk factor for the carriage of abnormal often

COMBATING DRUG RESISTANCE IN THE INTENSIVE CARE UNIT (ICU)

Deepak RoshaSenior Consultant, Department of Respiratory Medicine & Critical Care, Indraprastha Apollo Hospitals, Sarita Vihar,

New Delhi 110 076, India.Drug resistance of microbes has become a major stumbling block to treating patients successfully in the ICU.There is no doubt that microbes have the capacity to mutate or acquire drug destroying enzymes, but amultitude of errors by health care providers plays a major role in facilitating the development of resistance. Themaintenance of drug use discipline in closed ICUs and having a responsive microbiology department are thefirst steps towards prevention of microbe resistance. Having an infection control committee that is able tocollect and disseminate data is the next essential step. Education of health care providers to provide uniformityof health care according to set guidelines is the culmination of this towards the goal of minimizing thedevelopment of anti microbial resistance.

Key words: Drug resistance, ICU, Prevention of.

resistant microbes usually in the gut. Overgrowth ispromoted by the use of opiates, H2 blockers, proton pumpinhibitors and anti microbials [2].

CLOSED VS OPEN ICU

A major issue to be addressed is ICU policy anddiscipline. An open ICU is one where all consultants treattheir patients according to their own beliefs and learningand they have the power to overrule the intensivist who isusually a secondary consultant and can only makesuggestions. In such a set up enforcing antibiotic policyand introducing rational use of therapy becomes that muchmore difficult.

In the closed ICU system however, the intensivist is in-charge of all aspects of every case and will make alldecisions including antibiotic usage. In the latter set up itbecomes much easier to implement not only antibiotic butother policies that may directly or indirectly affectemergence of drug resistance [3].

INFECTIONS AND THE PATIENT

The microbiology of the patient changes as the lengthof time in ICU increase [4]. Studies have shown that

(a) in the first seven days the microorganisms of patientflora comprise Strep pneumonae, H influenza,Moraxella catarrhalis, C albicans, Staph aureus, Ecoli. These organism cause primary endogenousinfections including pneumonias in critically illpatients.It may be noted that whether C albicans cancause pneumonia at this stage is still underinvestigation. The incidence of these endogenousinfections is 55%.

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25 Apollo Medicine, Vol. 8, No. 1, March 2011

(b) after seven days the microbes have changed and areusually gram negative e.g. Klebseilla, Proteus,Enterobacter, Morganella, Citrobacter, Serratia,Citrobacter, Acinetobacter, Pseudomonas andMRSA. Infections by these microbes are consideredto be secondary endogenous and occur 30% of thetime.

(c) a third category of infection without any time frameis labeled exogenous and is attributed to poorhygienic measures or introduced by devices. Thisoccurs 15% of the time and the organisms are usuallythe GNB mentioned in (b) above.

It has been seen that while the patient is admitted forthe first seven days the organisms are usually sensitive tothird generation cephalosporins. Studies have shownhowever that if the patient is given prophylactic 3rdgeneration cephalosporins, resistant GNB and sometimesMRSA colonise the patient. Further studies have shownthat selective decontamination of gut by oral Polymyxin b,Tobramycin and Vancomycin can prevent the emergenceof these resistant bacteria. However as of now thesemeasures have not found universal consensus outside afew centres in Europe [5].

Microbiology department

The microbiology department has a pivotal role incombating anti–microbial resistance. The patients withsevere infections in the ICU come from three sources i.e.(a) community; (b) another hospital, and (c) samehospital.

Furthermore some of these patients may beimmunocompromised. The role of microbiology startsonce an infection has been identified. The source as wellas the site should be documented. The organisms areidentified and the drug sensitivity communicated to thetreating physician. The department should normallypublish a monthly in-house circular that shows thecommon microbes isolated from the identified sites andthe resistance pattern. The department should alsoimmediately communicate if a drug resistant microbe hasbeen isolated to the administration to take necessarymeasures to prevent the spread to other patients .Inaddition the department should be doing surveillancecultures from the throat and gut of potentially infectedpatients [6].

Antibiotic policy

The antibiotic policy of the hospital is formulated bythe infection control committee that includes themicrobiologist, intensivist, nursing and medical adminis-

trators. and infectious disease specialist [7]. The policyshould clearly spell out

(a) Initial antibiotic regimens to be used in seriously illpatients according to the immune status, length ofhospital stay, procedures done and site of infection ofthe patient .In the ideal situation antibiotics shouldonly be used where infection exists, however inpatients with systemic inflammatory response due tonon infectious causes it may be impossible to rule outsepsis. In such a situation antimicrobials with broadspectrum are required to be used. Antibiotic policywill create uniformity and remove irrationality fromsuch situations. Further the isolation of organismslow virulence should not justify the initiation ofantimicrobial therapy. In cases of fever of unknownorigin and in the absence SIRS it may be sufficient toremove indwelling catheters. Prophylacticantibiotics should be used for a short period of time[8].

(b) Samples should be obtained from blood, trachea orsputum, urine or any other infected site beforestarting antibiotics. Where the patient is already onantibiotics it may be prudent to wait 48hrs for aresponse before obtaining fresh cultures. In suchsituations cultures should be obtained before the nexttherapeutic dose of antibiotic is due .

(c) Antibiotic combinations which are consideredirrational or detrimental to the treatment should beconveyed to the treating physicians. Protocols shouldbe developed for specific infection and there shouldbe specific recommendations for first and secondline drugs and combinations to be used. This shouldbe according to the most common organisms causinginfection for that site in the region. The therapeuticdosing, drug interactions and adverse reactionsshould be monitored. It should be remembered thatadverse events such as nephrotoxicity, ototoxicity,and selection of resistant mutants are related toinadequate concentrations of antibiotics. There isusually an increase in body mass distribution in thecritically ill. Haemodynamic instability and renalfailure also affect drug elimination. Hence whereverpossible plasma drug concentrations especiallywhere the therapeutic window is small should beperformed [9].

(d) Information from the laboratory should be passed onas quickly as results are known to reduce the timethat broad spectrum antibiotics are used.

(e) Antibiotic tailoring to specific antibiotics once

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Apollo Medicine, Vol. 8, No. 1, March 2011 26

organism and sensitivity has been identified or deescalation therapy is an essential strategy to preventthe appearance of resistant organisms. As far aspossible once an organism and sensitivity are known,mono therapy should be used. However where thereis high incidence of treatment failure or chance ofemergence of resistance the use of two or moreantimicrobials is recommended [10].

(f) Antibiotic withdrawal policy once infection has beencontrolled and length of time antibiotics to be usedshould be rationalised. The first evaluation oftherapeutic response should be 72hrs after startingempiric treatment. This may be earlier if the clinicalresponse is unsatisfactory with further worsening ofthe patient’s condition. It is necessary to ensure thatthe anti microbials have good penetration into theaffected tissue and are given at appropriate intervalsto guarantee an adequate pk/pd relationship.Antibiotics are usually continued for 72 hrs aftersymptoms of fever, leucocytosis, haemodynamicinstability and pulmonary shunting have subsided. Inpatients infected with multi drug resistant organismsthe treatment may be prolonged to 14 days [11].

(g) Antibiotic cycling is an important strategy found tobe effective in limiting the emergence of resistance.This consists of periodic substitution of one class ofantibiotics for another or a combination having asimilar spectrum of activity but not sharing the samemechanism for the development of resistance.During each period or cycle of a few months durationonly antibiotics corresponding to that cycle may beused [13].

(h) Reserve antibiotic list where some antibiotics use isrestricted should be made. In the situation of openICUs it becomes important that some antibiotics areto be only used in special situations. This preservesthe spectrum of activity of these reserve antibiotics.

(i) Preemptive therapy policy consists of administeringantimicrobials before the appearance of clinicalsigns of infection. This concept was developed inhaematological patients using serological testswhich allows the diagnosis of infection before theappearance of clinical signs. Such patients are at ahigh risk for mortality especially from candidemia[14].

(j) Policy for antifungals agents and their empiric, preemptive as well as prophylactic use are required.

(k) Policy for selective decontamination of gut has beenmentioned above. Studies from Europe have found

this to be highly effective in limiting drug resistancebut the procedure is not yet universally accepted.

(l) Systems for monitoring implementation andenforcement should be in place. All monitoringsystems should never have a punitive but rather acorrective and educative approach.

MEASURES IN ICU

The ICU remains the home of super bugs resistant tomany of the major antibiotic groups. The ICU measuresfor emergence of drug resistance are firstly preventivewhich include policy measures set out above [15]. Inaddition the change of lines and catheters at regulatedintervals and their early removal are very important. TheICU staff should daily mark the number of days of lines,catheters and antibiotics have been used. The early use ofenteral feeding as apposed to parenteral feeding has asalutary effect on recovery from infection [16]. Theprolonged and indiscriminate use of proton pumpinhibitors predisposes the patient to lung infections. Asingle nurse for every patient is a very important measureand tends to curb the spread of organisms. Hand washingremains a corner stone of prevention of spread of resistantorganisms. A long term ICU facility for those patients whoare in a vegetative state is an expensive but necessarymeasure as these patients become reservoirs of resistantorganisms. The secondary measures are required whenresistant microbes have been isolated from the patient.Placing the patient in an isolation facility with negativepressure, dedicated nursing staff, hand washing ofattending doctors as well as gowns and mask becomenecessary [10]. Some measures for prevention ofventilator associated pneumonia have been found to beeffective. These include keeping the patient at least 30degrees upright as well as sub-glottic aspiration of theendotracheal tube or tracheostomy tube. On the other handthe use of silver impregnated endotracheal tubes and linecatheters as well as antibiotic coated catheters have notreduced late onset VAP or blood stream infectionsrespectively. Finally every instance of significant ICUfever should result in a thorough search for the cause inwhich blood counts, blood, urine, tracheal cultures andchest xrays as well as sonographic evaluation of abdomenis to be considered [17].

MEASURES IN THE COMMUNITY

It is very necessary to involve the general practionersin this fight to control drug resistance. The indiscriminateand irrational use of antibiotics sets the stage for thedevelopment of resistant and virulent organisms in thesociety itself. If possible the use of some higher antibiotics

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8. Heininger A, Meyer E, Schwab F, et al. Effects of longterm routine use of selective digestive decontaminationon antimicrobial resistance. Intenvive care med2006,32:569-676.

9. Burke JP. Infection control. A problem for patient safety. NEngl J Med, 2003, 348: 651.

10. Rosenthal VD, Maki DG, Salomao R. Device associatednosocomial infections in 55 intensive care uniys of 8developing countries. Ann Intern med 2006, 145(8): 582-589.

11. Stone PW, Hedblom EC, Murphy DM, et al. Theeconomic impact of infection control:Making thebusiness case for increased infection control resources.Am J infect control 2005,33(9):542-547.

12. Dodek P, Keenan S, Cook D, et al. Evidence basedclinical practice guidelines for the prevention of VAP. AnnIntern med 2004,141: 305-313.

13. Drakulovic MB, Torres A, Bauer TT, et al. Supine bodyposition as a risk factor for nosocomial pneumonia inmechanically ventilated patients: A randomized trial.Lancet1999, 354 (9193):1851-1858.

14. American Thoracic Society, Infectious Disease Society ofAmerica, Guidelines for the management of adults withhospital acquired, ventilator associated, and health careassociated pneumonia. Am J Respir Crit care med,2005,171: 388-416.

15. American College of chest physicians and society ofCritical care medicine Consensus conferencecommittee, Definitions for sepsis and organ failure andguidelines for use of innovative therapies in sepsis. Criticare med 1992, 20: 864-874.

16. Neuhauser MM, Weinstein RA, Rydman R, et al.Antibiotic resistance among gram-negative bacilli in USICUs. Implications for fluroquinolone use, JAMA,2003,289: 885-888.

17. Akinci E, Colpan A, Bodur H, et al. Risk factors for ICU-acquired imipenem-resistant gramnegative bacterialinfections, J Hosp Infect,2005,59: 317-323.

should be restricted to hospital only, or only allowed inculture proved cases outside the hospital. This of courserequires responsible behaviour from physicians andenforcement of laws by government. Education of thecommunity, monitoring of over the counter drugsdispensation by chemists and monitoring of prescriptionsby medical council is also necessary.

CONCLUSION

A brief attempt has been made to outline the mammothtask of controlling and combating drug resistance in theICU. It cannot be done by one individual but requires thecollective will of the whole community and hospitals tocombat this growing menace.

REFERENCES

1. Langer M, Cigagada M, Mandelli M. Early onseypneumonia: A multicenter study of intensive care units,Intensive care medicine,1987, 13: 342-346.

2. Balthussen A, Kindler CH. Citation classics in critical caremedicine. Intensive care med, 2004, 30:902-910.

3. Stoutenbeek CP. Prevention of pneumonia in an ICU, Critcare med, 1990,18: 1190-1191.

4. Craven DE, Hjalmarson K. Prophylaxis of VAP: changingculture and strategies to trump disease, Chest 2008,134:898-900.

5. Valles J, Artigas A, Rello J, et al. Continuous aspiration ofsubglottic secretionsin preventing VAP, Ann int med,1995,122:179-186.

6. Collard HR, Saint S, Matthay Ma. Prevention of VAP: anevidence based systematic review, Ann Intern med 2003,138:494-501.

7. Stoutenbeek CP, van Saene HKF. Non antibioticmeasures in the prevention of VAP, SEmin Respir Infec,1997,12: 294-299.

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