Resistencia Antimicrobiana en Unidades de Cuidado Intensivo de Bogotá, Colombia, 2001-2003

Current Anacsthesia & Critical Care (2001) 12, 41d47 ^ 2001 Harcourt Publishers Ltd doi:10.1054/cacc.2001.0321, available online at http://www.idealibrary.com on

FOCUS ON: MANAGEMENT OF INFECTIONS IN THE CRITICALLY ILL

Antimicrobial resistance in the intensive care unit: the use of oral non-absorbable antimicrobials may prolong the antibiotic era P. B. Baines*, J. MeyerR and M. A. de la CalS *Department of Paediatric Intensive Care, Royal Liverpool Children’s Hospital, Alder Hey, Liverpool, UK, RDepartment of Anaesthesia and Intensive Care, University Hospital of Munster, Munster, Germany and SDepartment of Intensive Care, University Hospital of Getafe, Madrid, Spain

KEYWORDS antimicrobial resistance, intensive care unit, oral non-absorbable antimicrobials

Summary Antimicrobial resistance is a significant problem in the intensive care unit. Ill patients carry abnormal bacteria, amongst which are the causative organisms of many of the nosocomial infections. Overgrowth of these bacteria predisposes to infection. Further, the excretion of systemically administered antibiotics into the gut selects resistant bacteria from this population. In eliminating overgrowth, oral non-absorbable antibiotics prevent infections and prevent the development of antibacterial resistance. This paper discusses the limited effect of traditional approaches in preventing antibiotic resistance. These rely on restriction of classes of antibiotics used, or by restricting antibiotic use by more specific (often invasive) diagnostic techniques (such as protected brush specimens) for the diagnosis of pneumonia. In contrast we describe the experience of three centres using oral non-absorbable antibiotics finding that antibiotic resistance is not a significant clinical problem. In one 20-bed paediatric intensive care, admitting 1000 children per year, of 390 admissions who stayed more than four days 12 episodes of infection (in eight individuals) were caused by antibiotic resistant bacteria. Oral non-absorbable antibiotics prevent both infections and the emergence of antibiotic resistant bacteria. ^ 2001 Harcourt Publishers Ltd

PRINCIPLES BEHIND THE CONCEPT Nowadays a major clinical problem facing the intensive care team is, antimicrobial resistance.1 We believe that the focus of studies should be on clinical aspects of the antimicrobial resistance problem as opposed to concentrating upon molecular-biological mechanisms of antimicrobial resistance. Several stages occur in the development of the carriage of antimicrobial resistant micro-organisms. First, it has only been recently learnt that illness severity is the most important independent risk factor for carriage of abnormal, often resistant, bacteria.2,3 Healthy individuals have innate mechanisms which clear abnormal bacteria.4 Unhealthy individuals carry abnormal micro-organisms in throat and gut and, where present, skin lesions. The

Correspondence to: PBB.

predominant site of carriage of abnormal bacteria is the gut. Second, for carriage of abnormal flora to occur, the patient must have been exposed to the abnormal microorganisms. Patients may either carry abnormal flora on admission (import) or the flora may have been normal on admission and then abnormal microbes acquired whilst on the unit (acquisition). Third, following exposure, ill patients may develop carriage i.e. persistent presence in throat and/or gut. Healthy individuals do not become sustained carriers of abnormal flora. Finally, abnormal carriage inevitably leads to overgrowth of abnormal flora in the critically ill patient. Overgrowth of abnormal flora represents a serious problem in the intensive care unit (ICU) for three reasons: (1) overgrowth is required for the carriage of a resistant strain amongst the sensitive population; (2) overgrowth is required for the endogenous supercolonization/infection of the individual patient;

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(3) overgrowth of resistant microbes promotes dissemination throughout the unit via the hands of carers. These four features, disease severity, exposure, carriage and subsequent overgrowth are the reasons why the ICU is the epicentre of the resistance problem.

Illness severity Illness severity is pivotal in the development of the abnormal carrier state. Over 30 years ago, it was first demonstrated that carriage of abnormal aerobic Gramnegative bacilli (AGNB) was a characteristic of disease.5 Healthy individuals carry only their indigenous Escherichia coli in the rectum6 whilst disease encourages oropharyngeal and gastrointestinal carriage of abnormal AGNB. Approximately one third of patients with chronic underlying conditions such as diabetes, alcoholism and chronic obstructive pulmonary disease (COPD) have been shown to carry abnormal flora.7}9 Previously well patients, who require ventilation for over 5 days, may become carriers following an acute insult, e.g. road traffic accident (RTA), burns, meningococcal infection, pancreatitis or acute liver failure.10 Modes for predicting the risk of mortality were developed for both paediatric (Paediatric Risk of Mortality; PRISM and Paediatric Index of Mortality; PIM) and adult (Acute Physiology and Chronic Health Evaluation; APACHE and Simplified Acute Physiological Score; SAPS) ICU patients to assess illness severity in a more quantitative manner during the eighties. Using these scoring systems a correlation between abnormal carriage of resistant micro-organisms and risk of mortality has been established. In a paediatric unit, children who carried antibiotic-resistant AGNB had higher maximal PRISM scores (6.47$4.85) compared with those patients who were free from resistant AGNB 3.76$3.87).2 Whilst one third of ICU patients with an APACHE II score of 515 were abnormal carriers of AGNB,11 the abnormal carrier state significantly increased to 50% in an ICU population with an APACHE II score of 527.12 In a mixed medical surgical ICU,3 one third of the study population who were free from abnormal AGNB on admission, acquired and became carriers of multiresistant Acinetobacter baumannii and Klebsiella pneumoniae, and again a high SAPS score (13$4.6 vs 11.3$6 in non-carriers) was the independent risk factor. The same concept applies to the abnormal carrier state of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Whilst MRSA and VRE may be only transiently present in the otherwise healthy carer,13,14 the SAPS score was significantly higher in ICU patients who carried MRSA compared with those carrying methicillin-sensitive S. aureus (MSSA) (SAPS of 11.5$35 vs 10.2$3.3, P(0.045).15 Case control studies showed significant associations between VRE carriage and

CURRENT ANAESTHESIA & CRITICAL CARE severity of illness (APACHE II of 13.1 in the case patients vs 8.0 in the controls).16 In summary, the evidence from the literature shows that it is primarily the patient’s illness that causes the conversion of carriage of normal into abnormal flora.

Microbial exposure In comparison with animate sources, i.e. patient carriers, the importance of inanimate sources, e.g. equipment or air, as an origin of abnormal flora is minimal.17,18 Patients are a main reservoir of abnormal microorganisms. It is highly unlikely that short-stay patients ((4 days) contribute to the spread of abnormal flora. Patients who stay 54 days, again emphasizing the impact of illness severity, are responsible for the dissemination of abnormal flora. Faecal carriage is generally accepted to be more important as a reservoir of abnormal bacteria then both oropharyngeal and nasal carriage, for the simple reason that there is a larger quantity of AGNB, MRSA and VRE found per g of faeces than per ml of saliva or nasal secretions. Recent epidemiological studies of resistance on ICU show that of all resistant strains between 30 and 50% are imported by patients, requiring intensive care, in their admission flora.19}22 Healthcare workers, although not a source of abnormal micro-organisms, transmit them between patients; therefore patients with normal flora may acquire abnormal flora. Caring for a patient, e.g. bathing, nappy changing, leads to high contamination levels of hands of up to 106 microbes per cm2 of finger surface.23 Handwashing with 0.5% chlorhexidine in 70% alcohol has been shown to clear hands of abnormal micro-organisms only if the contamination level is 4104 micro-organisms per cm2 of finger surface.24 At higher levels of contamination even diligent handwashing may leave 100 abnormal microorganisms per cm2 of finger surface. This explains how bacteria are transmitted between patients on a busy unit even though handwashing has been rigidly implemented. These quantitative aspects of the impact of handwashing explain why it does not abolish transmission, but only reduces it. Whereas handwashing has been demonstrated to control transmission of shigella and E. coli 0157 : H7, high level pathogens generally present in faeces at concentrations of (105/g,25,26 spreading of the potential pathogen MRSA present in overgrowth ('105/g of faeces) is not controlled by handwashing alone.27

Acquisition/carriage Acquisition [the presence of a potentially pathogenic microorganism (PPM) in one sample only] invariably leads to carriage (sustained presence of PPM in two or

ANTIMICROBIAL RESISTANCE IN THE ICU

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more successive samples) in the diseased individual.9 Healthy people are exposed daily to PPM, acquiring them mainly via food and beverages, then rapidly clearing them. Should a healthy person become unwell due to an insult e.g. RTA, meningococcal disease, this transient presence of PPM, invariably in very low concentrations per ml of saliva and/or g of faeces, may develop into carriage. Amongst apparently healthy carers, minor illness such as upper respiratory tract infections may promote carriage of MRSA due to the persistence of mucositis.28 Staff with chronic diseases, e.g. diabetes, COPD and alcoholism are at high risk of becoming carriers of ICU-associated PPM. In the absence of a break in the skin surface barrier, e.g. tracheostomy, gastrostomy or burns the prime site for acquisition and subsequent carriage is the oropharynx.5,29 AGNB and S. aureus, both resistant and sensitive to methicillin, actively adhere to the oropharyngeal mucosae. In contrast faecal carriage is a more passive process.30,31 Experimental work shows that PPM carried in the oropharynx express fronds or pili from their cell wall whilst identical AGNB isolated from the faeces lack pili.30 Acquisition almost always occurs during the first week of a patient’s ICU stay when their first line of defence against carriage is breached most easily due to underlying disease and invasive ICU procedures.3,22,32 Patients who require long-term intensive care ('1 week) may acquire ICU PPM and develop carriage at any time during their stay as long as their defence against carriage becomes impaired due to their ongoing underlying condition. Handwashing will have no effect whatsoever, regardless of compliance, on patients who carry AGNB, MRSA and MSSA on admission. This may explain the lack of evidence that hygiene alone significantly reduces the rates of pneumonia and septicaemia on ICU.33 It must be stressed that health carers should comply with handwashing as it plays a role in the reduction of PPM transmission between patients, reducing secondary endogenous and exogenous infections in a particular subset of longstay patients(51 week).

excreted via saliva, bile and mucus into throat and gut. Antimicrobials with a spectrum of activity which includes the normal indigenous anaerobic flora suppress and disrupt the balance of ecology in the patient which leads inevitably to overgrowth.36 Interruption of the enterohepatic cycle due to impaired motility increases faecal levels of antibiotics. Some antibiotics (flucloxacillin,37 amoxycillin,4 macrolides,38 beta-lactams and beta-lactamase inhibitors,39 and carbapenems40) are relatively more active against the indigenous flora and will cause greater disruption than others (cephradine,41 cefotaxime,42 aminoglycosides, polymyxins and amphotericin B43). In general, it is the newer more potent antibiotics, including carbapenems and quinupristin/ dalfopristin, that cause greater elimination of normal bacteria. Clinical features of overgrowth, caused by using antibiotic guidelines which disregard maintenance of a healthy bacterial ecology, include cutaneous candidiasis (in infants nappy rash)39 and diarrhoea due to Clostridium difficile.38 Whilst handwashing reduces transmission of PPM the topical application of non-absorbable antibiotics aims to prevent acquisition. Should overgrowth already have been established, topical non-absorbable antibiotics will eliminate PPM. Polymyxin and tobramycin clear AGNB, amphotericin B clears yeasts. Topical vancomycin clears MRSA.

Overgrowth

TRADITIONAL APPROACH TO ANTIMICROBIAL RESISTANCE

Overgrowth defined as carriage of PPM in concentrations5105 PPM/ml of saliva or g of faeces represents a serious problem for the critically ill patient and the intensive care unit. Overgrowth is encouraged by patient related factors such as impaired gut motility,34 failure of the gastric exocrine function leading to a gastric pH of '4,35 and poor swallowing with pooling of saliva. ICU interventions further promote overgrowth, i.e. opiates cause intestinal stasis, endotracheal intubation promotes overgrowth in saliva compounded by the use of muscle relaxants. Antibiotics, even after parenteral administration, are

Conclusion Concentration of the most ill patients in an enclosed environment encourages dissemination of all types of micro-organisms including resistant PPM. Resistant PPM are predominantly imported but may also be acquired nosocomially. In ill patients with overgrowth handwashing fails to control transmission. Frequent use of multiple antimicrobials which disregard the normal indigenous flora promotes overgrowth with resistant bacteria. For all these reasons the ICU is the epicentre of antimicrobial resistance.45

The traditional approach is based on two pillars; antibiotic restriction and hygiene, including handwashing and isolation.

Antibiotic restriction There is evidence relating antimicrobial usage to emerging resistance.46 Carriage in throat and gut and colonisation of internal organs, by PPM, are not treated. Only infection is treated (parenterally) to limit the use of antibiotics. Despite widespread attempts to limit the use

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of systemic antibiotics over 70% of all patients who stay more than 3 days on ICU will receive them.47 In the absence of surveillance to identify carriage of PPM, parenteral potent antibiotics are necessarily used in a blunderbuss fashion, conspiring to create the optimal conditions to produce antimicrobial resistance. With this approach we have seen successive waves of antibiotics rendered ineffective as resistance develops. The selective pressure exerted by the third generation cephalosporins, including cefotaxime, ceftriaxone and ceftazidime selected for Enterobacter spp and Pseudomonas aeruginosa. The subsequent introduction of the fluoroquinolones active against all AGNB led to resistance amongst P. aeruginosa, A. baumannii and to the emergence of the non-aeruginosa strains, e.g. S. maltophilia, and B. cepacia. A similar spectrum of micro-organisms has been selected by the newer most potent carbapenems. The prevailing belief that the pharmaceutical companies will always find the ‘superdrug’ for the ‘super-bug’ has been shattered. There have been no totally new systemic antibiotics with a completely unique mode of action since nalidixic acid in 1962.48 There are two approaches to controlling antibiotic usage. Increasing the specificity of the diagnosis of pneumonia, 30% of all ICU infections, by invasive techniques and scheduled changes of antibiotic classes. In a recent French randomized trial comprizing of 204 patients managed invasively with protected specimen brush, vs 209 patients managed conventionally with tracheal aspirates, the resistance problem was identical 61.3% vs 59.8% of isolates, despite significantly less use of antibiotics in the invasive group.49 In a short-term American study, 6 months of ceftazidime administration was followed by 6 months of ciprofloxacin administration and a comparison made.50 There was a significant reduction in the incidence of pneumonia due to resistant AGNB (4% vs 0.9%; P"0.013). The non-randomized design is a fundamental flaw confirmed by the difference in the aetiology of the causative agents. During ceftazidime treatment there was an outbreak of intrinsically resistant Serratia, in addition there were five viral and three Aspergillus pneumonias, i.e. 15/41 pneumonias were inappropriately treated by ceftazidime. During ciprofloxacin treatment there were a total of 22 pneumonias, only one of which was viral. The difference in pneumonia is no longer significant when comparing the appropriately treated pneumonias, i.e. 26 and 21. A Belgian audit describes a change from ceftazidime and ciprofloxacin to cefepime in response to a resistant Enterobacter problem.51 Although the resistant Enterobacter problem decreased threefold, a high rate of resistance to cefepime and other antipseudomonal agents amongst P. aeruginosa isolates persisted.

CURRENT ANAESTHESIA & CRITICAL CARE A third study in a paediatric unit evaluated the resistance problem during a scheduled change program from ceftazidime into piperacillin and tazobactam.52 In a fundamental change surveillance samples of throat and rectum were obtained as well as diagnostic samples, the aim being to compare the endemic reservoir of resistant AGNB. Despite a 96% reduction in ceftazidime use the density of carriage of ceftazidime-resistant AGNB carriage increased through a 19-month period. These data show that conventional approaches to antibiotic restriction or change are ineffective.53 A proactive approach by periodically, bimonthly, alternating classes of antimicrobial empirical treatment has been proposed contrasting the reactive scheduled change. This remains to be fully evaluated.54

THE SDD APPROACH As a development of the underlying concepts, outlined above, that ill patients will develop overgrowth of abnormal flora which is exacerbated by the administration of systemic antibiotics that disregard normal flora, our approach has four components: (1) twice weekly microbiological surveillance of throat and gut flora; (2) eradication of overgrowth with appropriate topical non-absorbable antimicrobials; (3) pre-eighties systemic antimicrobial agents that respect the ecology are used for empirical treatment when necessary for a maximum period of 5 days; (4) high standards of hygiene to control transmission of PPM. The hypothesis that control of overgrowth of PPM by SDD will control resistance has been tested in both paediatric and adult settings.55,56 In the 20-bed PICU at Alder Hey Children’s Hospital, Liverpool, UK the antibiotic policy consists of using pre-eighties antimicrobial agents that respect ecology.55 Prophylaxis in cardiac and general surgery included three doses of peri-operative teicoplanin/netilmicin, and cefotaxime/metronidazole, respectively. Blind therapy was based on cefotaxime and/or gentamicin for 5 days. Children showing oropharyngeal and/or intestinal overgrowth of AGNB yeasts and MRSA received oral non-absorbable polymyxin E, tobramycin, amphotericin B, or nystatin, and vancomycin, respectively, throughout their PICU stay. Surveillance cultures of throat and rectum were obtained on admission, and afterwards twice weekly to detect the carrier state of resistant bacteria. Diagnostic samples were obtained on clinical indication only. A total of 353 patients (median age 3 months, PIM score 0.070, stay 8 days) were responsible for 390 admissions resulting in 4688 PICU days. 36% were

ANTIMICROBIAL RESISTANCE IN THE ICU

medical, 38% cardiac surgical and 26% general surgical. On average per month, 20 full days of glycopeptide therapy were dispensed per 100 patient days (i.e. a monthly density of 20%). Cephalosporins and aminoglycosides were administered at a monthly density of 50 and 40%, respectively. During all but 3 months, the monthly density of topical polymyxin E, tobramycin, amphotericin B and vancomycin was higher (at 60%) than the density of the parenteral antimicrobials. Systemic antifungals were administered to only five patients over 1 year. The predominant resistant bacteria carried in the gut were: MRSA, Enterobacter and Citrobacter species resistant to ceftazidime, Klebsiella and Enterobacter species resistant to tobramycin. 60% of them were imported. Monthly, between four and 10 patients with carriage of resistant microbes were present in the PICU (Fig. 1). A total of eight patients had 12 infections due to resistant micro-organisms, MRSA, Klebsiella and P. aeruginosa (Fig. 2). There were four wound infections and two line infections of exogenous development (3;MRSA, 3;P. aeruginosa) in four children. One child had a secondary endogenous septicaemia with Klebsiella and three children were admitted with resistant microorganisms (Klebsiella, Enterobacter, MRSA) causing five primary endogenous infections. Methicillin-resistant Staphylococcus aureus (MRSA) has always been endemic in the medical/surgical ICU of the University Hospital of Getafe in Madrid, Spain.56 The manoeuvre of oral vancomycin for the eradication of oropharyngeal and gastrointestinal carriage was evaluated in patients requiring minimally 3 days of ventilation, the endpoint being endemicity control. Over a period of 3 years, 604 patients were assessed: 140 patients without oral vancomycin acted as the control group, oral vancomycin was given to 218 patients when their surveillance cultures yielded MRSA, and oral vancomycin was given to 206 patients as prophylaxis immediately on admission to the ICU. The median age of the study population was 61 years, SAPS II 39, length of stay 19 days, and overall mortality 29%. Although the intervention both prophylactic and therapeutic

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Figure 2 Density of patients with infections due to resistant microorganisms (March 1 1999}Feb 29 2000). The density is defined as the number of patients infected with resistant microorganisms per month of 100 patient days. *䊊 *, total; }䊉}, resistant.

controlled MRSA endemicity, the prophylactic mode was more effective both clinically and microbiologically. There were significantly less diagnostic samples positive for MRSA in both vancomycin groups: 44 patients had positive diagnostic samples in the control group (31%), compared with 37 (14%) and five (2%) patients in the intervention groups. Interestingly, none of the patients who received vancomycin prophylactically had surveillance samples yielding MRSA in overgrowth, i.e. 105 MRSA per ml or g, whilst 52% of patients were treated with oral vancomycin being carriers, still had throat and rectal swabs with MRSA in overgrowth. The sequential designealbeit not randomizedeis an accepted method for outbreak control. The safety of SDD relies upon resistance not emerging against the SDD antimicrobials in long-term use. A recent meta-analysis57 examining 33 randomized SDD trials involving 5727 patients confirmed the virtual absence of any reported resistance over a period of more than 10 years (1987}1997), and of subsequent superinfections and/or epidemics with multiresistant strains. Similar data is obtained from three other studies58}60 in which resistance during SDD was the endpoint over periods of 2, 2.5 and 7 years. Two further studies60,61 evaluating the emergence of resistant microorganisms after stopping SDD failed to show any negative effect. The virtual absence of a resistance problem is due to the eradication of resistant bacteria carried in the alimentary canal following the shift from solely systemic antimicrobials towards the combination of systemic and oral non-absorbable antimicrobials.62

CONCLUSION

Figure 1 Density of patients carrying resistant bacteria (March 1 1999}Feb 29 2000). The density is defined as the number of patients carrying resistant microorganisms per month of 100 patient days. *䉭e, methicillin-resistant Staphylococcus aureus ; * 䊐e, aerobic Gram-negative bacteria; }䊏}, total.

The ICU is the epicentre of the resistance problem. The use of solely systemic antibiotics, whether restricted or not, maintains an abnormal population of bacteria amongst which resistance is encouraged. The eradication of the reservoir of abnormal bacteria located in the gut has been shown to be effective in significantly reducing morbidity, mortality and resistance.

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