Infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens, particularly Klebsiella pneumoniae, are increasing. The epidemiology of ESBL-producing K. pneumoniae, the mechanisms of resistance, and treatment strategies for infections caused by these organisms are reviewed.
Infections caused by multidrug-resistant Gram negative bacilli that produce extended-spectrum β-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.
The genus Klebsiella is a member of the Enterobacteriaceae family. Klebsiella spp are ubiquitous in nature and can be found in the natural environment (e.g., water and soil) and on mucosal surfaces of mammals.4 Common sites of colonization in healthy humans are the gastrointestinal tract, eyes, respiratory tract, and genitourinary tract.4
K. 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.
Extended spectrum β-lactamase enzymes were first described in K. pneumoniae and Serratia marcescens isolates in 1983 in Europe6 and in K. 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. In the United States, the proportion of K. 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.1,2 Of 824 K. pneumoniae strains isolated from 15 hospitals in New York City during 1999, 34% expressed ESBL enzymes.8
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. Currently, about 80 different capsular (K) antigens are known. 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-α-2/3-mannose or L-rhamnose-α-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-β 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. Thus, Gram negative bacilli containing these plasmids are multidrug-resistant.12 Furthermore, these plasmids are mobile genetic elements and can be transmitted between Gram negative bacilli of different species in vivo.13 During a 30-month outbreak of ESBL-producing K. oxytoca in an NICU, the plasmid from K. oxytoca spread to K. pneumoniae, E. coli, Enterobacter cloacae, and Citrobacter freundii.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. coli, K. pneumoniae, and K. 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 μg/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. pneumoniae.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.14
Outbreaks of ESBL-producing organisms have been described. Asymptomatic patients colonized with ESBL-producing K. 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. Outbreaks of ESBL-producing K. pneumoniae in NICUs have been notable for high attack rates and large numbers of colonized infants.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
The importance of Gram negative bacilli as major cause of hospital-acquired infections in NICU patients has been well documented. K. 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. pneumoniae.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 1999, 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. pneumoniae infections can be challenging and is evolving. To date, there have been no clinical trials that evaluate the comparative efficacy of antibiotics in the treatment of infections caused by these pathogens. The type of ESBL enzyme produced and the site and severity of infection are important considerations in determining antimicrobial therapy.18,31 Therefore, active surveillance for ESBL-producing organisms is critical to describe fully the local epidemiology of a given institution and/or referring centers.
Broad-spectrum cephalosporins were initially developed to withstand chromosomal and some plasmid-mediated β-lactamase enzymes. However, the emergence of ESBL-producing bacteria has limited the usefulness of broad-spectrum cephalosporins in the management of serious infections caused by these pathogens, as there are reports of therapeutic failures and high mortality rates associated with the use of broad-spectrum cephalosporins, even when in vitro susceptibility is reported. Cephalosporins are therefore not recommended for the treatment of bloodstream and serious infections caused by these pathogens.19,32,33 However, cephalosporins have been used successfully to treat less serious infections such as UTIs and pneumonia.18,34
β-Lactamase inhibitors such as tazobactam and clavulanic acid have been shown to inhibit ESBL enzymes in vitro.34,35 The combination of tazobactam with an extended spectrum penicillin, such as piperacillin (Zosyn®), has broad-spectrum antimicrobial activity against a wide variety of bacteria including ESBL-producing bacteria.36 Piperacillin/tazobactam has been used successfully to treat bloodstream infections in preterm infants caused by ESBL-producing K. pneumoniae.37 In addition, piperacillin/tazobactam has been used successfully to treat UTIs.31,37,38 In contrast, therapeutic failures with piperacillin/tazobactam have been documented. Treatment failures have occurred for a variety of reasons that include: the presence of a large abscess presumably containing a large number of organisms, “hyperproduction” of ESBL enzymes by the infecting strain, or infection caused by a porin-deficient mutant which limited antimicrobial access into bacteria.24,39 In the absence of information on the innate resistance determinants of bacterial isolates, β-lactam-β lactamase inhibitors should be used with caution when treating serious infection caused by ESBL-producing K. pneumoniae as in vitro susceptibility may not necessarily predict in vivo efficacy. In contrast, the empiric use of β-lactam-β lactamase inhibitors in intensive-care units appears to have a small, but significant protective effect and reduces infections caused by ESBL-producing K. pneumoniae.40 Increased morbidity and mortality and prolonged hospitalization can result from ESBL-producing K. pneumoniae infection mostly due to a delay in appropriate antimicrobial treatment.20,41
The use of other non-β-lactam antibiotics, such as quinolones, has been effective in the treatment of infections caused by ESBL-producing organisms in animal models.42 However, rare plasmids that contain the ESBL gene also contain resistance genes for quinolones.43 Reports have shown a close association between ESBL production and ciprofloxacin resistance, as 18% of ESBL-producing strains are resistant to ciprofloxacin.43 Further clinical evaluations of quinolones in the treatment of serious infections caused by ESBL-producing organisms should be reported. While quinolones can induce permanent damage to the cartilage of juvenile animals44 such toxicity has not been observed in children. Nevertheless, until pharmacokinetic studies and safety studies of quinolones are performed in preterm infants, the use of quinolones should be limited.
Currently, the carbapenems, that is, imipenem and meropenem, are the only class of antimicrobials that have consistently been effective against ESBL-producing K. pneumoniae. Carbapenems remain stable in the presence of ESBL enzymes and the small compact size of carbapenems allows easy passage through porins into Gram negative bacilli. Thus, carbapenems are often the preferred antimicrobial agent for the treatment of serious infections caused by ESBL-producing organisms. While imipenem was used to treat severe infections during an outbreak of ESBL-producing Klebsiella spp, its use was associated with the emergence of imipenem-resistance Acinetobacter spp.18
Infection Control Strategies
To control the spread of ESBL-producing pathogens, appropriate infection control interventions should be implemented for all patients who are infected or colonized with ESBL-producing bacteria. These interventions include effective hand hygiene and instituting contact precautions for all colonized and infected patients.45 Health-care workers in NICUs should not be permitted to wear artificial fingernails. During a prolonged outbreak, a broader investigation to search for additional reservoirs in colonized patients, health-care workers, and the environment may be needed.5 Also important is the judicious use and control of antimicrobials, particularly the restricted use of broad-spectrum cephalosporins.18,46 This is particularly important in NICUs that use cefotaxime to treat late-onset sepsis.
In conclusion, infections with ESBL K. pneumoniae are increasing, particularly among patients in ICUs. This pathogen is usually multidrug-resistant and there are limited treatment options available. Active surveillance for ESBL-producing pathogens in high-risk populations should be performed using appropriate antimicrobial techniques. Disease progression has occurred while on treatment with antibiotics to which there is in vitro susceptibility. The carbapenems, that is, imipenem and meropenem, are safe and effective antibiotics for the treatment of severe ESBL-producing K. pneumoniae infection in preterm infants.
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Empfehlung zur Prävention nosokomialer Infektionen bei neonatologischen Intensivpflegepatienten mit einem Geburtsgewicht unter 1500 g
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz (2007)