David rubenstein md 1 and lisa saiman md, mph 1 ,2 infections caused by multidrug resistant gram negative bacilli that produce extended spectrum lactamase esbl enzymes have been reported with increasing frequency in intensive care units and are associated with significant morbidity and mortality. 1 ,2 because of resistance to numerous antimicrobial agents, treatment can be challenging. 3 we review the literature with respect to the epidemiology of pathogens, particularly klebsiella pneumoniae. Which express esbl enzymes, molecular mechanisms of resistance, and treatment strategies and highlight the potential discrepancy between in vitro susceptibility testing and in vivo efficacy.

epidemiology

the genus klebsiella is a member of the enterobacteriaceae family.

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klebsiella spp are ubiquitous in nature and can be found in the natural environment e.g. 4 common sites of colonization in healthy humans are the gastrointestinal tract, eyes, respiratory tract, and genitourinary tract. Pneumoniae has emerged as an important cause of hospital acquired infections, especially among patients in the neonatal intensive care unit and mortality rates can be as high as 70%. 5 over the last two decades, the incidence of infections caused by multidrug resistant klebsiella strains has increased. Pneumoniae and serratia marcescens isolates in 1983 in europe 6 and in k.

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Pneumoniae and escherichia coli isolates in 1989 in the united states. 7 since then, there has been a marked increase in the incidence of bacteria that produce esbl enzymes. Pneumoniae strains resistant to ceftazidime increased from 1.5% in 1987 to 3.6% in 1991, and by 1993 as many as 20% of strains were resistant to ceftazidime in some teaching hospitals. Pneumoniae strains isolated from 15 hospitals in new york city during 19, 34% expressed esbl enzymes.

virulence factors

numerous virulence factors have been described in klebsiella spp. Extracellular capsules are essential to virulence the capsular material forms thick bundles of fibrillous structures that cover the bacterial surface in massive layers. 4 this protects the bacterium from phagocytosis by polymorphonuclear granulocytes and prevents killing by bactericidal serum factors via the complement mediated cascade. Although klebsiella capsular polysaccharide cps has generally been thought to mediate virulence, it has been shown more recently that the mannose content of the cps confers the degree of virulence. For example, strains that contain repetitive sequences of mannose 2/3 mannose or l rhamnose 2/3 l rhamnose are of lower virulence.

These mannose sequences are recognized by the surface lectin of macrophages and the organism is more efficiently ingested and killed by opsonin independent phagocytosis. 9 in addition to the capsule, there are about five somatic or o antigens, fimbrial and nonfimbrial adhesins, which serve as virulence factors. The fimbriae or pili are nonflagellar, filamentous projections on the bacterial surface that mediate attachment of the organism to respiratory, gastrointestinal, and urinary tract mucosal cells.

Additional virulence determinants for klebsiella spp include the ability of the organism to scavenge iron from the surrounding medium using secreted siderophores, that is, enterochelin and aerobactin. These are high affinity, low molecular weight iron chelators that competitively take up iron bound to host proteins. 10

molecular mechanisms of resistance

esbl are plasmid mediated enzymes that hydrolyze oxyimino lactam agents such as third generation cephalosporins and aztreonam. 11 these plasmids also carry resistance genes to other antibiotics including aminoglycosides, chloramphenicol, sulfonamides, trimethoprim, and tetracycline.

12 furthermore, these plasmids are mobile genetic elements and can be transmitted between gram negative bacilli of different species in vivo. Oxytoca in an nicu, the plasmid from k. oxytoca spread to k. 14 over 100 different esbl enzymes have been identified, each with a preferential substrate. Thus, an esbl producing isolate may be resistant to ceftazidime, but susceptible to cefotaxime.

As a result, esbl producing isolates may not be detected if susceptibility testing is limited to a single third generation cephalosporin. The national committee for clinical laboratory standards nccls recommends routine screening for esbl activity in e. Oxytoca isolates by determining susceptibility to several cephalosporins including cefpodoxime, cefotaxime, ceftriaxone, and ceftazidime. 15 ,16 if an isolate is resistant to any one of these agents, that is, mic 2 g/ml, confirmatory tests for an esbl enzyme are performed by demonstrating increased susceptibility to cefotaxime or ceftazidime in the presence of clavulanic acid, as clavulanic acid inhibits esbl enzymes and lowers the mic of the cephalosporins. However, bacteria with esbl containing plasmids remain susceptible to the carbapenems, that is, meropenem and imipenem, and cephamycins such as cefoxitin and cefotetan.

risk factors for acquisition of esbl producing pathogens
epidemiological studies suggest that the increasingly widespread use of third generation cephalosporins is a major risk factor that has contributed to the emergence of esbl producing k. 17 ,18 ,19 several additional risk factors for colonization and infection with esbl producing organisms have been reported and include: arterial and central venous catheterization, gastrointestinal tract colonization with esbl producing organisms, prolonged length of stay in an intensive care unit, low birth weight in preterm infants, prior antibiotic use, and mechanical ventilation. 20 ,21 ,22 carriage of this organism increases dramatically among hospitalized patients, as colonization rates increase in direct proportion to the length of stay. Pneumoniae can serve as reservoirs for this pathogen with subsequent patient to patient spread via the hands of health care workers. In addition, contaminated patient care items and artificial fingernails worn by health care workers have been implicated in transmission. 23 ,24 ,25 ,26 most studies have demonstrated a poor adherence to infection control policies as an important factor. Pneumoniae in nicus have been notable for high attack rates and large numbers of colonized infants.

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26 the neonates at greatest risk for colonization are those with a longer length of stay, a lower estimated gestational age and/or a lower birth weight. 14

clinical presentations

the importance of gram negative bacilli as major cause of hospital acquired infections in nicu patients has been well documented. Pneumoniae can cause both early onset and, more commonly, late onset sepsis, conjunctivitis, hospital acquired pneumonia, urinary tract infections utis , and surgical site infections. 4 ,27 approximately 4% of episodes of late onset sepsis in very low birth infants and 6% of overall infections in the neonatal icu population are caused by k. 28 ,29 according to the most recent national nosocomial infection surveillance system data, k.

Pneumoniae has been noted to cause 2.9% of bloodstream infections, 2.9% of eye, ear, nose and throat infections, 9.8% of gi tract infections, 5.7% of pneumonia, and 6.3% of surgical site infections in the nicu. 30 as demonstrated by the cdc/national association of children's hospitals and related institutions nachri point prevalence survey conducted in 19, k. Pneumoniae caused 1.7% of bloodstream infections, 20% of respiratory tract infections, 8.3% of utis, and 5.6% of other infections in patients in nicus. 29
treatment of esbl producing organisms
management and treatment of esbl producing k.