antibacterial resistance in the intensive care unit: mechanisms … · 2017-04-12 · intensive...

Antibacterial resistance in the intensive careunit: mechanisms and management

T S J Elliott* and P A Lambert**Department of Clinical Microbiology, University Hospital Birmingham NHS Trust, QueenElizabeth Hospital, Birmingham, UK and ^Department of Pharmaceutical and Biological Sciences,Aston University, Birmingham, UK

The incidence of multiple antimicrobial resistance of bacteria which causeinfections in the intensive care unit is increasing. These include methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, penicillin-resistant Streptococcus pneumoniae and cephalosporin and quinolone resistantcoliforms. More recently, pan antibiotic resistant coliforms, includingcarbapenems, have emerged. The rapidity of emergence of these multipleantibiotic-resistant organisms is not being reflected by the same rate ofdevelopment of new antimicrobial agents. It is, therefore, conceivable thatpatients with serious infections will soon no longer be treatable with currentlyavailable antimicrobials. Strict management of antibiotic policies andsurveillance programmes for multiple resistant organisms, together withinfection control procedures, need to be implemented and continuouslyaudited. As intensive care units provide a nidus of infection for other areaswithin hospitals, this is critically important for prevention of further spread andselection of these resistant bacteria.

Correspondence to:Prof T S J Elliott,

Department of ClinicalMicrobiology, Queen

Elizabeth Hospital,Edgbaston, Birmingham

B15 2TH, UK

Antibiotic resistance was first encountered clinically in the form ofpenicillin-resistant staphylococci in the early 1940s. Single- and multi-drug resistance mediated by plasmids, which could be transferredbetween organisms in the gastrointestinal tract was subsequentlyreported in the late 1950s. By the mid-1970s, these resistance genes hadbecome more widespread and included commensal organisms present inthe respiratory and genito-urinary tracts of many hospitalised patients.Despite the significant improvements made in the performance ofantibiotics and enhanced infection control measures, this spread ofantibiotic resistance has continued throughout the 1980s and 1990s.

Two factors control the spread of resistance: the ability of organismsto transfer, acquire and rearrange resistance genes and the selectivepressure generated by the use of broad spectrum antibiotics. Theinteraction of these two components of the 'drug resistance equation'

British Medical Bulletin 1999,55 (No. 1): 259-276 C The British Council 1999

Intensive care medicine

has resulted in the current position where there are only a limitednumber of antimicrobials available to treat some infections, with theprospect of untreatable organisms in the future1*2. Indeed, a recent SelectCommittee of the House of Lords highlighted the potential problemsassociated with the emergence of antimicrobial resistant micro-organisms in many areas of medicine3. This report also outlined thedifficulties in the management of patients with infections caused bythese micro-organisms and the need to develop strategies for preventingfurther emergence and spread of multi-resistant strains. This currentreview summarises the threat of antimicrobial resistant bacteria inintensive care units (ICU), the organisms and mechanisms involved, andapproaches which can be employed for prevention.

Micro-organisms

Gram-positive bacteria

Methicillin-resistant Staphylococcus aureus (MRSA)4-5 and vancomycin-resistant enterococci (VRE)6-7 have emerged as major nosocomialpathogens. Vancomycin is currently the most reliable treatment forinfections caused by MRSA. However, the potential transfer of resistancegenes from VRE to the MRSA may leave few therapeutic options in thefuture. Whilst the deliberate transfer of vancomycin resistance proveddifficult to achieve in the laboratory, naturally-occurring vancomycin-intermediate 5. aureus (VISA) have now been reported from a number ofcentres8*9. VRE, as well as providing a reservoir of vancomycin resistancegenes, can also cause infections which are difficult to treat, with somestrains showing resistance to all major classes of antibiotic. Other Gram-positive cocci pose a less dramatic but significant threat. Coagulase-negative staphylococci (CNS) are an important cause of infectionsassociated with prosthetic devices and catheters. Although they displaylower virulence than S. aureus, they have intrinsic low-level resistance tomany antibiotics (including P-lactams and glycopeptides). The additionalability of many of these bacteria to produce slime makes treatment ofprosthetic associated infections difficult and often requires removal of theinfected prosthesis or catheter. Streptococcus pneumoniae, regarded asfully sensitive to penicillin for many years, has now acquired the genes forresistance from oral streptococci. The prevalence of these resistant strainsis increasing rapidly worldwide. This will limit the therapeutic options inserious pneumococcal infections, including meningitis and pneumonia,particularly when acquisition of resistance to other groups of antibioticsalso occurs10.

260 British Medical Bulletin 1999;55 (No. 1)

Antibacterial resistance

Gram-negative bacteria

Antibiotic resistant aerobic Gram-negative bacilli cause significantnumbers of infections in ICU. Of these Pseudomonas aeruginosa, and theEnterobacteriaceae, including Escherichia coli and Enterobacterspecies,account for the majority of isolates where resistance has emerged.Resistance mechanisms in these organisms are partly intrinsic, with thelow permeability of the Gram-negative cell envelope, but moreimportantly due to the presence of resistance genes. Genes encoding highlevel resistance to multiple antibiotics can assemble on plasmids which aretransmissible between organisms. Smaller genetic elements termedtransposons found within plasmids and in chromosomes containresistance genes which, together with integrase genes, promote their owntransfer both between plasmids and from plasmids to chromosomes.Other small mobile genetic elements related to transposons are termedgene cassettes and integrons. These are important determinants of thespread of resistance to fJ-lactams, aminoglycosides, trimethoprim andchloramphenicol among the Gram-negative aerobic bacilli.

types of infections in intensive care units

Besides the patient's underlying disease, the main risk factors associatedwith the development of ICU-acquired infection include increased length ofICU stay, mechanical ventilation, trauma, intravascular and urinarycatheterisation, and stress prophylaxis. Most of the infections in patientson an ICU result from the patient's own endogenous flora. However, cross-infections may occur with outbreaks occasionally being recognised. Micro-organisms which may cause outbreaks include S. aureus, Clostridiumdifficile, Acinetobacter species and E. coliu>n.

Pneumonia, septicaemia and postoperative sepsis are the commonesttypes of infections which result in patients requiring intensive care treat-ment13. In addition, up to 50% of patients being treated in ICU will alsoacquire nosocomial infection14'15, which are associated with a relativelyhigh degree of morbidity and mortality16. Certain pathogens also morecommonly cause a high mortality rate. For example, in a review of surgicalICU patients with Xanthomonas spp. infections17, the associated mortalitywas significantly higher (P < 0.05) (26.9%) as compared to other patientswithout sepsis (10.3%). The types of infection in ICU patients were clearlyidentified in a recent large prevalence survey carried out on 40% ofEuropean units18. Of all the patients studied, 44.8% were reported to beinfected and 20.6% had an ICU-acquired infection. Infection of the lowerrespiratory tract (65%), urinary tract (18%) and bloodstream (12%) were

British Medical Bulletin 1999,55 (No. 1) 261


the most frequent sites of sepsis. Micro-organisms associated with theseinfections included Enterobacteriaceae (34%), 5. aureus (30%), P.aeruginosa (29%), CNS (19%) and fungi (17%).

Antimicrobial resistant organisms in intensive care units

The identification of antimicrobial resistance patterns of organismspresent in ICUs is important to prevent further spread. This type ofsurveillance will facilitate the choice of appropriate antimicrobial therapyand the implementation of infection control policies which may furtherrestrict the development of resistance. The European Epic Study18

recorded antimicrobial resistance patterns for S. aureus, P. aeruginosa andCNS isolated from patients on ICU. Of the 5. aureus isolated, 60% weremethicillin resistant (MRSA). Of the S. aureus causing bacteraemias, 72%were MRSA. The resistance patterns of P. aeruginosa were multiple andincluded resistance to gentamicin (46%), imipenem (21%), ceftazidime(27%), ciprofloxacin (26%) and a ureido-penicillin (37%). Many of theCNS were also resistant to a wide range of antimicrobials. Of all the CNSisolated, 73% were resistant to one or more of the following antibiotics;methicillin (70%), cefotaxime (69%), gentamicin (66%), vancomycin(3.5%) and teicoplanin (9.3%).

More recently, multiple antimicrobial resistant organisms includingacinetobacters and VRE which may also be resistant to teicoplanin havebeen reported in ICUs. Although acinetobacters have relatively lowpathogenicity, their intrinsic resistance to many widely used antimicrobialagents, their ability to spread easily from patient-to-patient and to survivein the hospital environment have contributed to their increasing clinicalimportance especially in the ICU19. In a recent review of ICUs in the UK20,45 out of 70 units reported the presence of acinetobacters, the majoritybeing sporadic cases. Acinetobacters were most commonly associatedwith colonisation and infection of the lower respiratory tract.

In a further review21 of the antimicrobial susceptibility rates amongstaerobic Gram-negative bacilli isolated from patients in ICUs, resistance tothird generation cephalosporins was further shown to be an emergingproblem, particularly with Klebsiella pneumoniae and Enterobacter species.These bacteria were frequently also resistant to aminoglycosides andciprofloxacin. In the US, as in Europe, new approaches for treating patientswith serious infections in ICUs are being driven by similar increasingnumbers of cephalosporin and other antimicrobial-resistant Gram-negativeaerobic bacilli. In a survey of nearly 400 hospital ICUs in North America,resistance rates for Klebsiella species and Enterobacter species to thirdgeneration cephalosporins were shown to have increased during the1990s22, approaching 40% with some strains. The mechanism of resistance

262 British Medical Bulletin 1999.55 (No. 1)


is related to production of extended spectrum |3-lactamases which appearsto have arisen through overuse of third generation cephalosporins.

Multi-drug resistant P. aeruginosa has also become endemic within somespecialised ICUs, particularly those treating burns patients23. P. aeruginosa,which is resistant to antibiotics including piperacillin, ceftazidime,aztreonam, imipenem, ciprofloxacin and aminoglycosides, has beenreported on a burns unit. The epidemic strain persisted for several monthsand resulted in various severe infections.

In a further study on the distribution of resistance patterns and serotypesof P. aeruginosa, multiple antibiotic-resistant strains have been shown tobe more frequently present in the ICU than other areas within a hospital24.This reflects the level of antimicrobial selective pressure in the intensivecare situation as compared to other clinical areas within the hospital.

The emergence of strains of Gram-negative aerobic bacilli, includingacinetobacters, which produce broad spectrum P-lactamases or stable de-repressed hyper producers of chromosomal (antpC) cephalosporinase arenow making the carbapenems in many cases the only effective antibiotictreatment for this type of infection25. The more recent reports ofcarbapenem resistance in coliforms is, therefore, a cause for concern.

Besides Gram-negative organisms, multiple antibiotic resistant CNS andMRSA as identified in the Epic Study are commonly isolated from patientsin the ICU. More recently, VREs have been isolated from patients inICUs26. If the MRSA also becomes resistant to vancomycin, the emergenceof a glycopeptide resistant MRSA on ICU will result in major difficultiesin managing any associated infections.

Mechanisms of antimicrobial resistance

Methicillin-resistant Staphylococcus aureus

S. aureus illustrates the interaction between the genetic and selectivepressure components of the drug resistance equation. Resistance originallyarose through selection of strains which destroyed penicillin G byproduction of a p-lactamase. This enzyme probably originated bymutation of carboxypeptidase genes used in assembly of the vitalpeptidoglycan component of the organism's cell wall. Development andwidespread use of pMactamase-resistant penicillins, such as methicillin andlater the isoxazolyl penicillins (cloxacillin, dicloxacillin and flucloxacillin),encouraged the emergence of MRSA strains4. These owe their resistance,not to production of P-lactamase, but to expression of an altered penicillinbinding protein (PBP) target enzyme involved in cell wall synthesis (themecA transpeptidase). This enzyme exhibits greatly reduced susceptibilitytowards the penicillins and can replace the function of the susceptible

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enzymes. Separate selective pressure through the use of other antibioticshas led to the emergence of strains resistant to other major classes ofantibiotics, including the aminoglycosides and tetracyclines, resulting inmost MRSA strains being multi-drug-resistant. MRSA strains are notintrinsically more virulent than sensitive strains, most S. aureus isolatesproduce a wide range of virulence factors which are independent of theirantibiotic resistance genes. The major threat posed by MRSA strains liesin the dependence for their control upon the glycopeptide antibiotics,vancomycin and teicoplanin. Hence the recent acquisition ofvancomycin resistance genes from enterococci is of major significance27.

Vancomcyin-resistant enterococci

The enterococci (Enterococcus faecalis and Enterococcus faecium) areintrinsically resistant to a wide range of antibiotics, including theaminoglycosides and cephalosporins. Although they are not highlyvirulent, they have emerged as significant nosocomial pathogens inpatients with compromised immunity. Glycopeptides are among the fewantibiotics which are effective against the enterococci. They blockbacterial cell wall synthesis by binding tightly to the D-alanyl-D-alanineregion of the peptidoglycan precursor before it is incorporated into thecell wall6. VRE were first reported in 1988 and are now encountered withincreasing frequency, particularly in association with multiple antibioticusage. A number of different resistance phenotypes are recognised: vanA,vanB and vanC. VanA is characterised as an inducible, high levelresistance to both vancomycin and teicoplanin. The genes responsible forthe vanA phenotype are carried on a transposon, a highly mobile geneticelement found on many different plasmids in enterococci and able totransfer rapidly between strains. Of the nine genes carried on thetransposon three (vanA, vanH and vanX) are responsible for producingan altered peptidoglycan precursor containing D-alanyl-D-lactate insteadof the usual D-alanyl-D-alanine. The modification in the precursor resultsin much weaker binding and no effective inhibition of cell wall synthesis.The other genes carried by the transposon are involved in the induction ofthe vanA phenotype by vancomycin and teicoplanin. VanB resistanceoccurs by a similar overall mechanism involving a separate cluster ofgenes, resistance is induced by vancomycin but not by teicoplanin. Thegenes responsible for vanB resistance have been detected on plasmids inclinical isolates which transfer resistance between strains by conjugation.

The emergence and dissemination of glycopeptide resistance genes inenterococci over the last 10 years has resulted in clinical isolates whichare resistant to all antibiotics of otherwise proven efficacy. Theincreasing incidence of VRE strains among clinical isolates of



enterococci places them as important nosocomial pathogens. Of equalimportance is their potential to act as reservoirs of resistance genes fortransmission to MRSA.

Streptococcus pneumoniae

Until recently the pneumococcus, an encapsulated Gram-positiveorganism, had been exquisitely sensitive to penicillin G, with minimuminhibitory concentrations in the region of 0.001 ug/ml. Resistance firstappeared in the 1960s in Papua New Guinea, Australia and the US. Sincethen, isolates with MICs between 1 and 16 [Ag/ml have been widelyreported with incidences rising rapidly in some countries. Multi-drug-resistant strains were initially isolated in South Africa in the late 1970sand are now encountered worldwide, for example in Spain and SouthAfrica 18% of penicillin-resistant strains are resistant to two or moreclasses of antibiotics. The genes for resistance to tetracycline, erythro-mycin and chloramphenicol appear to have been acquired on conjugativetransposons. By contrast, penicillin resistance has resulted from a trans-formation process in which DNA encoding large regions of the penicillinbinding protein targets from other organisms (especially oral streptococci)has been incorporated into the chromosome to form functional, resistantnew 'mosaic' PBP genes. Unlike methicillin resistance in S. aureus,penicillin resistance in pneumococci results from alterations in severaldifferent PBPs and the mosaic genes may contain DNA from variousdonors (including Streptococcus sanguis and Streptococcus oralis).

Gram-negative aerobic bacilli

Resistance in Gram-negative bacteria to pMactams is caused chiefly by theacquisition of plasmids encoding genes for enzymes which inactivate theantibiotics by hydrolysis. Many different p-lactamases have beenidentified. The emergence and spread of the plasmids has closely followedthe development of the p-lactam antibiotics. Each improvement in 0-lactamase stability of penicillins and cephalosporins has been followedwithin about 5 years by the appearance of strains producing enzymes fortheir destruction. The TEM-1 enzyme is produced by over 90% ofampicillin-resistant strains of E. coli. Plasmids carrying TEM-1 cantransfer freely among the Enterobacteriaceae and P. aeruginosa. Followingthe introduction of cephalosporins such as cefuroxime, cefotaxime andceftazidime, which are resistant to TEM-1, strains producing enzymescapable of their destruction appeared. Examples of these are TEM-12 andTEM-26, in which key amino acid residues in the original TEM enzyme

British Medical Bulletin 1999;55 (No 1) 265


have been altered by mutation to produce an extended-spectrum ofactivity. Over 20 different extended spectrum enzymes have been reportedand they are particularly prevalent in clinical isolates of K. pneumoniae.

Not all P-lactamases responsible for clinical resistance to p-lactams areplasmid-mediated. Many Gram-negative aerobic bacilli contain chromo-somal genes for the expression of the ampC (3-lactamase which is inducedby the presence of the pMactam antibiotics. Mutations in the genes whichregulate the expression of ampC result in excess amounts of the enzyme tobe produced. The enzyme only hydrolyses cephalosporins slowly, but acombination of a high level of expression and binding (trapping) of theantibiotics and the restricted permeability barrier of the outer membraneresults in significant resistance. Clinical isolates exhibiting this form ofresistance include strains of Enterobacter cloacae, Citrobacter freundii,Acinetobacter species and P. aeruginosa.

The introduction of the carbapenems, imipenem and meropenem, hasencouraged the emergence of strains which produce carbapenemases. Theseare p-lactamases with a particular affinity for the carbapenems and havebeen reported in many isolates of Bacteroides fragilis, Stenotrophomonas(formerly Xanthomonas) maltophilia, E. cloacae, Serratia marcescens,Aeromonas spp. and P. aeruginosa. Many of these P-lactams are metallo-enzymes, containing zinc atoms at their active site, but those produced by5. marcescens and E. cloacae contain a serine residue at this site. Most arechromosomally mediated, their transfer onto plasmids will undoubtedlyspeed up the spread to other organisms.

The aminoglycosides are another groups of antibiotics which aresusceptible to inactivating enzymes. Instead of destroying these antibioticsby hydrolysis, the enzymes catalyse a chemical modification of hydroxyland amino groups on the aminoglycosides introducing acetyl, phosphoryland adenyl groups. The genes encoding the resistance are transferable.Resistance is widespread, in particular in the Enterobacteriaceae and P.aeruginosa. Individual strains can produce more than one modifyingenzyme and the overall resistance phenotype can be enhanced by a reducedpermeability to the aminoglycoside.

Another mechanism of resistance to antibiotics involves the removal(extrusion or efflux) of the drugs from organisms before inhibition of thetargets can take place. It involves the function of a cytoplasmic membranetransport system that actively removes the drugs from the cells. Thismechanism is currently most commonly encountered against the tetra-cyclines in clinical isolates of streptococci and staphylococci. Of increasingconcern is the susceptibility of other groups of antimicrobial agents,including the macrolides and quinolones, to efflux mechanisms in Gram-positive and Gram-negative bacteria28. Efflux may even occur across theouter membrane of Gram-negative bacteria and influence the susceptibilitytowards p-lactams, which do not cross the cytoplasmic membrane29.



Prevention of infections associated with multipleantimicrobial resistant bacteria

Screening

Identification of the causative organism before therapy is commencedpermits selection of specifically targeted antibiotics. It is also importantthat ICUs should have a surveillance programme for antibiotic resistantorganisms so that empiric treatment can be selected based on knownsensitivity patterns and can be altered immediately following the identi-fication of a new resistance pattern of any organisms on a unit. Care mustbe taken in the use of appropriate sensitivity tests for detection ofresistance. Although culture methods are widely used, new moleculartechniques offer the prospect of rapid and sensitive detection of thepresence of resistance genes30-31.

Infection control in intensive care units

Microbial colonisation of critically ill patients is a prerequisite in manyconditions for the development of subsequent sepsis. This process isfacilitated by the use of invasive techniques including urinary andintravascular catheters, and ventilation equipment. The oropharynx andgastrointestinal tract are important sources of aerobic Gram-negativebacilli which may cause various infections including ventilatory associatedpneumonia32. The skin in comparison is a primary source of organisms,including the CNS, which are the main cause of intravascular catheterrelated infections33"34, bacteraemia and septicaemia35. Prevention strategiesfor catheter-related sepsis have been produced34 and include the use ofcatheters impregnated with antimicrobial agents.

Nosocomial outbreaks of multiple antibiotic resistant bacteria havebeen associated with failures in infection control. For example,contamination of ventilation equipment was shown to be related to anoutbreak of acinetobacter36. Following surveillance, the organism wasdetected in output ducts of a ventilator machine despite the use ofbacterial filters. To overcome this particular outbreak ventilator equip-ment had to be sterilised internally.

The widespread use of antibiotics also selects out antibiotic resistantorganisms which can become endemic within units. This is seen not onlywith the Gram-negative aerobic bacilli but also with MRSA and VRE.Outbreaks of these organisms can occur with spread being primarily frompatient-to-patient via the hands of medical personnel. Fomites, includingequipment and faulty air handling systems, can also enable organisms tospread around units37. It is vitally important that appropriate and timely



cleaning schedules, including curtain changes and air handling plants aswell as equipment, are in place. The development of alternatives tocurtains, including cleanable glass panels which can be changed fromopaque to transparent on demand, should be encouraged further.

Simple approaches for the prevention of spread of infection on the ICUhave included attention to correct and timely handwashing. Theappropriate use of antiseptic handwash preparations is also important.For example, the use of a triclosan handwash has been shown to eliminateMRSA from a neonatal ICU38. Similarly screening patients prior toadmission to ICUs for carriage of specific resistant organisms can assist incontrol. The carriage of MRSA, for example, has been shown to identifythose patients at increased risk of subsequent postoperative MRSAinfection39. Eradication schedules and other infection control measures,including barrier nursing, can then be commenced earlier. Ideally, patientswith multiple antibiotic resistant organisms in an ICU should be strictlyisolated and cohort nursed. However, this is not commonly practised dueto limitations of suitable facilities and financial support. Handwashingbetween patient contacts should, however, be mandatory to preventtransmission even when no multiple antibiotic resistant organisms arepresent on a unit. Staff health also needs to be considered. For example,the use of effective topical agents such as mupirocin and chlorhexidine forMRSA staff carriers can reduce the likelihood of spread40.

The highest percentage of micro-organisms which are resistant toantimicrobial agents in hospitals has been shown to be predominantlylocated in patients in the ICU. Indeed a significant sequential decrease inthe percentage of resistant organisms has been shown in studies onpatients located in ICUs, non-ICU patients and outpatients41. It is,therefore, evident that resources allocated to control antimicrobialresistance should continue to be focused in the hospital, particularly in theICU situation. Indeed the emergence of antibiotic resistant pathogenssuggests that to contain the problem of infections associated with theseorganisms, measures must primarily be focused towards carefulsurveillance of resistance, optimising antibiotic use and the prevention oftransmission through effective infection control practices42.

Selective decontamination of the digestive tract with non-absorbent antibiotics

Many nosocomial infections in ICU are associated with carriage of Gram-negative aerobic bacilli in the gastrointestinal tract which may result inendogenous infections as described above. Selective decontamination ofthe digestive tract (SDD) is a method used for the prevention or eradicationof carriage of these organisms in the gastrointestinal tract. Many trials ofSDD have been published and several have shown a significant reduction



in the incidence of nosocomial Gram-negative infections43. The impact ofSDD on morbidity and mortality however is less clear. Gastinne demon-strated in a randomised, double-blind, multi-centre study of patients receiv-ing mechanical ventilation that SDD did not improve survival in thesepatient groups44.

Where studies have tested the efficacy of SDD in ICU patients withmorbidity related infection as a main end point, many of the results havedemonstrated a reduction in infection rates but it is still unclear whetherthere is a decrease in mortality45. In a recent meta-analysis of trials of SDDa reduction in respiratory tract infections and overall mortality in severelyill patients was demonstrated. However, concern with the emergence ofantimicrobial resistance with the use of selective decontamination has beenraised46. Indeed, Lingnau demonstrated that bacterial resistance increasedwith the use of selective decontamination. It would, therefore, seem logicalthat the widespread use of SDD as a prophylactic approach for theprevention of Gram-negative aerobic bacilli infections should be limited tospecific high risk patients and not used widely.

Antibiotic policies

Antibiotic usage in ICU is relatively high due to the types of infectionswhich patients have and also the predominant organisms found in suchsituations. The use of antibiotics, particularly broad spectrum agents,selects out multiple antibiotic resistant micro-organisms, ranging fromPseudomonas species, Acinetobacter species, Klebsiella species and otherGram-negative aerobic bacilli to VRE and MRSA. Bacterial resistance to anumber of antibiotics may develop in a unit and these may colonise orinfect patients. It is, therefore, important to restrict the use of antibioticsand to be selective in the types of treatment schedules used. Before selectingan antibiotic, several factors need to be considered. Firstly, appropriatemicrobiological investigations must be carried out before the commence-ment of antimicrobial agents. This will enable directed antimicrobialagents to be given when the results of microbiology tests are available. Theimportance of obtaining cultures for microbiological investigation has beenclearly demonstrated in the recent report47 in which the influence ofrepeated bronchiolar lavage cultures on patients with ventilator associatedpneumonia was studied. Among 60 patients studied with microbiologicallypositive cultures, 44 were receiving inadequate antibiotic therapy with thecausative micro-organism being resistant to the prescribed current treat-ment. Mortality rates of patients who required changes to their antimicro-bial regimens was significantly higher as compared to those on appropriatetreatment.

For the empiric use of antibiotics, factors such as the site of infection,the types of organisms prevalent in a particular unit and the patient's



underlying disease, immune competence, liver and renal function alsoneed to be taken into account. If, for example, a central venous catheterassociated infection is thought to be the most likely source of sepsis thenantimicrobial agents directed against CNS and S. aureus need to beselected. Similarly, if a patient becomes septic following urinary catheter-isation, this is likely to be associated with a coliform and cover for theseshould, therefore, be selected. If a patient has a respiratory tract infectionwhich is community acquired the causative organisms are likely to includeS. pnewnoniae, Mycoplasma pnewnoniae, Haemophilus influenzae and,occasionally, Legionella pneumophila. Antimicrobial agents to provideappropriate cover for this type of infection may include the use ofcefotaxime and a macrolide. If, however, a patient has developed ahospital acquired pneumonia then conforms are more likely to be thecausative organisms and the antimicrobials need to be directed towardsthose which are prevalent in the ICU. If a patient has aspirated and sub-sequently developed pneumonia, metronidazole should be included in thetreatment regimens as anaerobes may be associated with the infection.

The effects of restricting selected antimicrobials with appropriatelycontrolled antimicrobial programmes have been studied48. Not only wasthe total use of parenteral antimicrobials decreased by nearly one-third butsusceptibility to all P-lactams and quinolone antibiotics subsequentlyincreased in isolates recovered from patients on the ICU. This is obviouslyan important strategy for the prevention of development of antimicrobialresistance.

New antimicrobials

Protection of existing agents against resistance mechanisms

A notable success in combating resistance to P-lactam antibiotics throughexpression of fi-lactamases has been the deployment of specific inhibitorsto protect the vulnerable drugs49. Clavulanic acid has been the mostsuccessful in this respect, used in combination with amoxyillin andticarcillin. Sulbactam has also been used in combination with ampicillinand tazobactam with piperacillin. Unfortunately not all p-lactamases aresusceptible to these inhibitors, for example the chromosomal ampCenzyme is not inhibited by clavulanic acid and the metalloenzymes whichdestroy carbapenems are not sensitive to any available inhibitors.Inevitably, following prolonged used of clavulanic acid, resistant forms ofenzymes previously sensitive have now emerged.

Some success in protecting aminoglycosides from inactivation bymodifying enzymes has been achieved. The aminoglycoside amikacin is amodified form of kanamycin which contains a protective substituent at the

270 British Medial Bulletin 1999;55 (No. 1)


position most frequently vulnerable to attack. This deliberately introducedmodification does not compromise the antimicrobial activity. Similarprotection of chloramphenicol against acetylation has been investigated bythe introduction of fluoro substituents but these chloramphenicolderivatives have not been developed further because of potential toxicityand poor pharmacokinetic properties.

With the recognition of efflux mechanisms of resistance, attention hasbeen directed towards the design of agents which are not transported bythe extrusion pumps50. The glycylcyclines are modified tetracyclines whichare not susceptible to efflux mechanisms. Another approach is to findcompounds which inhibit the efflux pumps, thereby protecting susceptibleagents from extrusion.

Modification of existing compounds and the search for agents withnovel mechanisms of action

A number of cephalosporins and carbapenems have been reported to beactive against MRSA, these compounds retain activity towards the mecAPBP. Similarly, some modified glycopeptides retain activity against vanAand vanB resistant enterococci51. Derivatives of vancomycin are also beinginvestigated for enhanced activity against the VRE52. Compounds withmechanisms of action that are distinct from those of the |3-lactams orglycopeptides have also been developed. The synergistic streptogramincombination of quinupristin and dalfopristin and the novel oxazolidinonesare the most promising examples53. These agents inhibit protein synthesisat sites which are separate from existing inhibitors. However, the potentialfor resistance development to these agents exists and has already beenencountered. Other promising groups of antibiotics include theeverninomycins and ketolides51"54. Newer quinolones with activity againstMRSA and VRE are also being developed51.

Summary

Antimicrobial resistance is increasing in many microbial pathogens,reflecting de novo selection due to antibiotic usage and pressure as well asthe spread of resistant organisms both in the community and in hospitals.This situation is occurring worldwide and has been reflected by theemergence of both Gram-positive and Gram-negative bacteria with theability to resist the action of many antimicrobial classes. The importantorganisms which are currently emerging include MRSA and VRE. Thepossibility of the emergence of pan-resistance in the MRSA, includingvancomycin, is of major concern particularly as VISA have already been



reported in Japan, the US and France55. Pan-resistance is more frequentlyseen in enterococci and some isolates of E. faecium att resistant to all 0-lactams, aminoglycosides and glycopeptides, leaving only antimicrobialagents still in development to use. These include the streptogramins,quinupristin and dalfopristin (Synercid®), and the oxazolidonones, forexample Linazolid®, as possible drugs of choice. Gene exchange can occurbetween enterococci and staphylococci and it is likely that high levelglycopeptide resistance will spread to MRSA and possibly S. pneumoniae.Multiple antibiotic resistance is also increasing in Gram-negative aerobicbacilli including Enterobacteriaceae which are becoming resistant to allgroups of antimicrobials. Even carbapenem resistance is being increasinglyreported in Acinetobacter species worldwide. P. aeruginosa resistant to P-lactams, aminoglycosides and quinolones have evolved and some strains arenow pan-resistant. Indeed plasmid-mediated carbapenems (carbapenem-destroying enzymes) have emerged in enterobacteria and Pseudomonasspecies in Japan56 which have resulted in resistance to all anti-pseudomonalpMactams. Other organisms including S. maltophilia and Burkholderiacepacia also have inherent ability for broad spectrum resistance. Theactivity of the quinolones is also being challenged with many Gram-negativeaerobic bacilli developing resistance by mutation of die gyrA subunit of theDNA gyrase target. More recently, an E. coli isolated with transferablequinolone resistance57 has been reported in Spain. This has importantimplications for further spread of resistance.

With the emergence of many antimicrobial resistant bacteria,particularly in ICUs, it is important that specific antimicrobial policieswith strict infection control measures are implemented and units arecontinuously monitored for the emergence of antimicrobial resistance. Ifthis action is not taken many patients will develop untreatable bacterialinfections.

Key points for clinical practice - antimicrobial resistance

• Antimicrobial resistance is becoming a widespread major problemin the intensive care unit.

• Awareness needs to be improved.

• Strategies for prevention need to be developed.

• Multiple antimicrobial-resistant organisms include:Acinetobacter speciesCoagulase-negative staphylococciEnterobacter speciesEscherichia coli



Pseudomonas aeruginosaStenotrophomonas ntaltophiliaStreptococcus pneumoniaeMethicillin-resistant Staphylococcus aureusVancomycin-resistant enterococci

Further antimicrobial-resistant organisms may develop andbecome widespread including:

Vancomycin-resistant Staphylococcus aureusPan-antibiotic resistant coliforms

Development of new antimicrobials is not keeping pace withthe rate of emergence of resistant organisms.

Patients with untreatable infections are a clinical possibility.

Key points for clinical practice - prevention of the emergenceof antimicrobial resistant organisms

• Develop care plans for treatment of infections including selectionof empirical antimicrobials based on surveillance cultures andalter according to subsequent microbiology results.

• Monitor for endemic organisms within units including fomitesand equipment.

• Restrict use of broad spectrum antibiotics and keep length oftreatment to minimum.

• Consider antimicrobial rotation.

• Design and implement strict infection control proceduresincluding handwashing, cohort nursing and cleaning schedules.

• Regularly review all procedures for possible transmission ofinfection.

• Consider infection control with any new proceduresincluding equipment.

Acknowledgements

We wish to thank Mary McDermott for expert secretarial support, CarolHouse for carrying out the literature searches, and Derek Healing foruseful comments.



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